Bifunctional heterocyclic compounds and methods of making and using same

ABSTRACT

The invention provides a family of bifunctional heterocyclic compounds useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents. The invention also provides methods of making the bifunctional heterocyclic compounds, and methods of using such compounds as anti-infective, anti-proliferative agents, anti-inflammatory, and/or prokinetic agents.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser. No. 11/359,820, filed Feb. 21, 2006 (allowed), which is a continuation application of U.S. application Ser. No. 10/671,326, filed Sep. 25, 2003, which incorporates by reference and claims priority to U.S. Patent Application Nos. 60/414,207, filed Sep. 26, 2002, and 60/448,216, filed Feb. 19, 2003.

FIELD OF THE INVENTION

The present invention relates generally to the field of anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents, and more particularly, the invention relates to a family of bifunctional heterocyclic compounds useful as such an agent.

BACKGROUND

The evolution of strains of cells or organisms resistant to currently effective therapeutic agents is an ongoing medical problem. For example, the development of cancerous cells resistant to chemotherapeutic drugs has long been recognized as a problem in the oncology field. Once resistant cells develop, the therapeutic regime, in order to remain effective, must be modified to introduce other chemotherapeutic agents. Another example of this resistance problem is the development of strains of microbial, fungal, parasitic and viral pathogens resistant to one or more anti-infective agents. As a result, there is still a need for new anti-proliferative and anti-infective agents that are effective against strains of cells or organisms that have developed resistance to currently available agents.

In the field of anti-infective agents, a variety of different antibiotics have been developed and approved for use in humans over the years. An oxazolidinone ring containing antibiotic known as linezolid (see, compound 1), available under the trade name Zyvox®, has been approved for use as an anti-bacterial agent active against Gram-positive organisms. Unfortunately, linezolid resistant strains of organisms are already being reported (Tsiodras et al. (2001) LANCET 358: 207; Gonzales et al. (2001) LANCET 357: 1179; Zurenko et al. (1999) PROCEEDINGS OF THE 39^(TH) ANNUAL INTERSCIENCE CONFERENCE ON ANTIBACTERIAL AGENTS AND CHEMOTHERAPY (ICAAC); San Francisco, Calif., USA, September 26-29).

Because linezolid is both a clinically effective and commercially significant anti-microbial agent, investigators have been working to develop other effective linezolid derivatives. Research has indicated that the oxazolidinone ring is important for linezolid activity. The literature commonly describes molecules having small groups substituted at the C-5 of the oxazolidinone ring, and early structure-activity relationships suggested that compounds with larger groups at the C-5 position were less active as anti-bacterial agents. As a consequence, it is believed that, in general, investigators have been reluctant to place large substituents at the C-5 position of oxazolidinone rings in anti-microbial agents.

International patent publication no. WO 01/81350 discloses a series of C-5 substituted oxazolidinones (see, general structure 2) where the acetamido group of linezolid was replaced, for example, with an optionally substituted N-linked 5-membered heteroaryl ring or an N-linked 6-membered heteroaryl ring. The 5-membered heteroaryl ring may contain either (i) one to three further nitrogen heteroatoms, or (ii) a further heteroatom selected from O and S together with an optional further nitrogen heteroatom; wherein the ring is optionally substituted on a C-atom by an oxo or thioxo group; and/or is optionally substituted on a C-atom by one or two C₁₋₄ alkyl groups; and/or on an available nitrogen atom (provided that the ring is not thereby quaternized) by C₁₋₄ groups. The N-linked 6-membered heteroaryl ring may contain up to three nitrogen heteroatoms in total, wherein the ring is substituted on a suitable C-atom by oxo or thioxo groups, and optionally substituted on any available C-atom by one or two C₁₋₄ alkyl groups.

In addition, International patent publication nos. WO 99/64416 and WO 00/21960 also disclose a series of 5-substituted oxazolidinones (see, general structure 3). In particular, WO 99/64416 discloses compounds having the general structure 3, where X is —O— or —S— and HET is a C-linked 6-membered heteroaryl ring containing 1 or 2 nitrogen atoms. WO 00/21960 discloses compounds having the general structure 3, where X is —N(H)— and HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S.

European Patent no. 0 097 469 B1 discloses intermediates of compound 4 which are useful in the synthesis of triazole anti-fungal agents of general structure 5. The intermediates may contain a disubstituted C-5 atom in the oxazolidinone ring, and the nitrogen atom of the oxazolidinone ring is a secondary amine.

Gregory and coworkers disclose the synthesis of a variety of oxazolidinone containing antibacterial agents (Gregory et al. (1989) J. MED. CHEM. 32: 1673-1681). Compound 6, a C-5 substituted five-membered heteroaryl derivative, was inactive as an antibacterial agent. This observation appears to be consistent with other oxazolidinone containing compounds that have the opposite stereochemical configuration at C-s relative to that found in linezolid.

Oxazolidinone compounds similar to those of compound 8 have been formed via decomposition of substituted nitrosoureas 7 and have been useful as anticancer agents (Mulcahy et al. (1989) EUR J. CLIN. ONCOL. 5: 1099-1104; Carmiati et al. (1989) BIOCHEM. PHARMACOL. 38: 2253-2258).

U.S. Pat. No. 6,034,069 discloses a series of 3′-N-modified 6-O-substituted erythromycin ketolide derivatives similar to compound 9. The aryl group attached to the aminosaccharide moiety (represented by a 3-pyridyl group in 9) was variable, and non-aryl substituents were synthesized as well.

Published German patent application DE 196 04 223 A1 discloses oxazolidinone ring-containing compounds of the general structure 10, where R₁ can be, in addition to other structures, a substituted or unsubstituted five-membered ring chosen from thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl and pyrrolidinyl.

U.S. Pat. No. 6,362,189 discloses antibiotic compounds having the general formula II. To the extent that the chemical moiety denoted by the symbol “G” may be an oxazolidinone ring, the ring may be substituted with a thiocarbonyl functionality, namely a —CH₂NHC(S)R₁.

International patent publication no. WO 99/63937 proposes the synthesis of multivalent macrolide antibiotics comprising a portion of a macrolide antibiotic linked via a linker to a portion of another known antibacterial agent. Two of the compounds proposed, although apparently not made or tested, include those shown below having the formulas 13a and 13b.

Notwithstanding the foregoing, there is still an ongoing need for new anti-infective and anti-proliferative agents. There is also an ongoing need for new anti-inflammatory agents, and new agents to treat gastrointestinal motility disorders.

SUMMARY OF THE INVENTION

The invention provides a family of compounds useful as anti-infective agents and/or anti-proliferative agents, for example, chemotherapeutic agents, anti-fungal agents, anti-bacterial agents, anti-parasitic agents, anti-viral agents, and/or anti-inflammatory agents, and/or prokinetic (gastrointestinal modulatory) agents, having the formula:

or pharmaceutically acceptable salts, esters, or prodrugs thereof. In the formula, p and q independently are 0 or 1. Also, A, at each occurrence, independently is a carbon atom, a carbonyl group, or a nitrogen atom. The B, D, E, and G groups can be selected from the respective groups of chemical moieties later defined in the detailed description.

In some embodiments, the invention provides a family of compounds having the formula:

or pharmaceutically acceptable salts, esters or prodrugs thereof. In the formula, p and q independently are 0 or 1. Also, A, at each occurrence, independently is a carbon atom or a nitrogen atom, provided that when one A is a nitrogen atom, the other A is a carbon atom. The B, D, E, and G groups can be selected from the respective groups of chemical moieties later defined in the detailed description.

In other embodiments, the invention provides a family of compounds having the formula:

or pharmaceutically acceptable salts, esters or prodrugs thereof. In the formula, p and q independently are 0 or 1. Also, A, at each occurrence, independently is a carbon atom or a nitrogen atom. The B D, E, and G groups can be selected from the respective groups of chemical moieties later defined in the detailed description.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the foregoing compounds and a pharmaceutically acceptable carrier. In yet another aspect, the invention provides a method for treating a microbial infection, a fungal infection, a viral infection, a parasitic disease, a proliferative disease, an inflammatory disease, or a gastrointestinal motility disorder in a mammal by administering effective amounts of the compounds of the invention or pharmaceutical compositions of the invention, for example, via oral, parenteral, or topical routes. In still another aspect, the invention provides methods for synthesizing any one of the foregoing compounds. In another aspect, the invention provides a medical device, for example, a medical stent, which contains or is coated with one or more of the foregoing compounds.

The foregoing and other aspects and embodiments of the invention may be more fully understood by reference to the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a family of compounds that can be used as anti-proliferative agents and/or anti-infective agents. The compounds may be used without limitation, for example, as anti-cancer agents, anti-bacterial agents, anti-fungal agents, anti-parasitic agents and/or anti-viral agents. Further, the present invention provides a family of compounds that can be used without limitation as anti-inflammatory agents, for example, for use in treating chronic inflammatory airway diseases, and/or as prokinetic agents, for example, for use in treating gastrointestinal motility disorders such as gastroesophageal reflux disease, gastroparesis (diabetic and post surgical), irritable bowel syndrome, and constipation.

1. DEFINITIONS

For the purpose of the present invention, the following definitions have been used throughout.

The carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C_(i-j) defines the number of carbon atoms present from the integer “i” to the integer “j”, inclusive. Thus, C₁₋₄ alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, and butyl, and isomeric forms thereof.

The terms “C₁₋₂ alkyl”, “C₁₋₃ alkyl”, “C₁₋₄ alkyl”, “C₁₋₅ alkyl”, “C₁₋₆ alkyl”, “C₁₋₈ alkyl”, “C₁₋₁₀ alkyl”, and “C₁₋₁₆ alkyl” refer to an alkyl group having one to two, one to three, one to four, one to five, one to six, one to eight, one to ten, or one to sixteen carbon atoms, respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and their isomeric forms thereof.

The terms “C₂₋₅ alkenyl”, “C₂₋₆ alkenyl”, “C₂₋₈ alkenyl”, and “C₂₋₁₆ alkenyl” refer to at least one double bond alkenyl group having two to five, two to six, two to eight, or two to sixteen carbon atoms, respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentdienyl, hexenyl, hexadienyl, heptenyl, heptdienyl, octenyl, octdienyl, octatrienyl, nonenyl, nonedienyl, nonatrienyl, undecenyl, undecdienyl, dodecenyl, tridecenyl, tetradecenyl and their isomeric forms thereof.

The terms “C₂₋₅ alkynyl”, “C₂₋₆ alkynyl”, and “C₂₋₈ alkynyl” refer to at least one triple bond alkynyl group having two to five, two to six, or two to eight carbon atoms, respectively such as, for example, ethynyl, propynyl, butynyl, pentynyl, pentdiynyl, hexynyl, hexdiynyl, heptynyl, heptdiynyl, octynyl, octdiynyl, octatriynyl, and their isomeric forms thereof.

The terms “C₃₋₄ cycloalkyl”, “C₃₋₆ cycloalkyl”, “C₅₋₆ cycloalkyl”, “C₃₋₇ cycloalkyl”, and “C₃₋₈ cycloalkyl” refer to a cycloalkyl group having three to four, three to six, five to six, three to seven, or three to eight carbon atoms, respectively such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof.

The terms “C₁₋₄ alkoxy”, “C₁₋₅ alkoxy”, “C₁₋₆ alkoxy”, and “C₁₋₈ alkoxy”, refer to an alkyl group having one to four, one to five, one to six, or one to eight carbon atoms, respectively attached to an oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms thereof.

The term “C₁₋₆ hydroxy” refers to an alkyl group having one to six carbon atoms, and isomeric forms thereof, attached to a hydroxy group.

The terms “C₁₋₃ acyl”, “C₁₋₄ acyl”, “C₁₋₅ acyl”, “C₁₋₆ acyl”, and “C₁₋₈ acyl” refer to a carbonyl group having an alkyl group of one to three, one to four, one to five, one to six, or one to eight carbon atoms, respectively.

The terms “C₁₋₄ alkoxycarbonyl”, and “C₁₋₆ alkoxycarbonyl” refer to an ester group having an alkyl group of one to four, or one to six carbon atoms, respectively.

The terms “C₁₋₆ alkylthio” and “C₁₋₈ alkylthio” refer to an alkyl group having one to six or one to eight carbon atoms respectively and isomeric forms thereof attached to a sulfur atom.

The term “C₁₋₃ alkylamino” refers to alkyl groups having from one to three carbon atoms attached to an amino moiety such as, for example, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, or ethylpropylamino and their isomeric forms thereof.

The term “Het” refers to 5 to 10 membered saturated, unsaturated or aromatic heterocyclic rings containing one or more oxygen, nitrogen, and sulfur forming such groups as, for example, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole, benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl, 1-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties may be substituted as appropriate.

The terms “halo” or “halogen” refers to a fluorine atom, a chlorine atom, a bromine atom, and/or an iodine atom.

The term “hydroxy protecting group” refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known (see, for example, T. H. Greene and P. G. M. Wuts (1999) PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3rd edition, John Wiley & Sons, New York). Examples of hydroxy protecting groups include, but are not limited to, acetate, methoxymethyl ether, methylthiomethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aromatic group and the like.

The term “aryl” refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.

The term “substituted aryl” refers to an aryl group, as defined herein, substituted by independent replacement of one, two, three, four, or five of the hydrogen atoms thereon with substituents independently selected from alkyl, substituted alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. More specifically, the substituents may be F, Cl, Br, I, OH, NO₂, CN, C(O)—C₁₋₆ alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂, CONH—C₁₋₆ alkyl, CONH-aryl, CONH-heteroaryl, OC(O)—C₁₋₆ alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl, OCONH₂, OCONH—C₁₋₆ alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)—C₁₋₆ alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl, NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—C₁₋₆ alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO₂—C₁₋₆ alkyl, SO₂-aryl, SO₂-heteroaryl, SO₂NH₂, SO₂NH—C₁₋₆ alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, CF₃, CH₂CF₃, CHCl₂, CH₂OH, CH₂CH₂OH, CH₂NH₂, CH₂SO₂CH₃, aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C₁₋₆ alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C₁₋₃ alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C₁₋₆ alkyl-thio, or methylthiomethyl. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term “arylalkyl group” refers to an aryl group attached to an alkyl group. An example of an arylalkyl group is a benzyl group.

The term “substituted arylalkyl group” refers to an aryl group or substituted aryl group attached to an alkyl group or a substituted alkyl group, provided that one or both of the aryl and alkyl groups are substituted.

The term “heteroaryl” refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one, two, or three ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

The term “substituted heteroaryl” refers to a heteroaryl group as defined herein, substituted by independent replacement of one, two, three, four, or five of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO₂, CN, C(O)—C₁₋₆ alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂, CONH—C₁₋₆ alkyl, CONH-aryl, CONH-heteroaryl, OC(O)—C₁₋₆ alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl, OCONH₂, OCONH—C₁₋₆ alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)—C₁₋₆ alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl, NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—C₁₋₆ alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO₂—C₁₋₆ alkyl, SO₂-aryl, SO₂-heteroaryl, SO₂NH₂, SO₂NH—C₁₋₆ alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, CF₃, CH₂CF₃, CHCl₂, CH₂OH, CH₂CH₂OH, CH₂NH₂, CH₂SO₂CH₃, aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C₁₋₆ alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C₁₋₃ alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C₁₋₆ alkyl-thio, or methylthiomethyl.

The term “heterocyclic” refers to heterocycloalkyl and heteroaryl. The term “substituted heterocyclic,” as used herein, refers to substituted heterocycloalkyl and substituted heteroaryl.

The term “macrolide” refers to any compound possessing a 14- or 15-macrocyclic ring, and derivatives thereof (such as keto, oxime, cyclic carbonate derivatives). These include, for example, compounds that are (or are synthetically derived from) known antibacterial agents including, but not limited to, erythromycin, clarithromycin, azithromycin, telithromycin, roxithromycin, pikromycin, flurithromycin, and dirithromycin.

In the formulas herein, a broken or dashed circle within a ring indicates that the ring is either aromatic or non-aromatic. A bond extending from a chemical moiety that is depicted as crossing a bond in a ring, but is not attached directly to a ring atom, indicates that the chemical moiety may be bonded to any atom of the ring. As to any of the above chemical moieties that contain one or more substituents, it is understood that such moieties do not contain any substitution or substitution patterns that are sterically impractical and/or synthetically unfeasible. In addition, the compounds of this invention include all stereochemical isomers arising from the substitution of these moieties.

The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. PHARM SCIENCES 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid), or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

The term “pharmaceutically acceptable ester” refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Other suitable ester groups include, for example, those derived from pharmaceutically acceptable alcohols, such as straight-chain or branched aliphatic alcohols, benzylic alcohols, and amino-alcohols. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, and methyl, ethyl, propyl, benzyl, and 2-aminoethyl alcohol esters.

The term “pharmaceutically acceptable prodrugs” refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the previously formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

The term “physiologically acceptable cation” refers to common, positively charged species such as (but not limited to) metals such as sodium, potassium, calcium, magnesium, zinc and the like. The cation can also be an organic species such as an amine salt. Non-limiting examples of such amine salts can be the protonated form of methylamine, ethylamine, cyclohexylamine, lysine, N-methylglucamine, diethanolamine, triethanolamine, tris-(hydroxymethyl)aminomethane, piperidine, morpholine, and the like.

The term “electron-withdrawing group” refers to groups well known to those in the art capable of pulling electron density towards the group and away from a source (such as an aromatic ring, an olefin, a carbonyl-like group or a sigma bond between two designated atoms). Examples of such electron-withdrawing groups are, for example, nitro, keto, formyl, acyl, halogens, carboxy, trihaloalkyl, sulfonyl and the like.

Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present invention also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

2. COMPOUNDS OF THE INVENTION

In one aspect, the invention provides compounds having the formula:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,

wherein

A, at each occurrence, independently is carbon, carbonyl, or nitrogen, provided at least one A is carbon;

Z is carbon, nitrogen, oxygen, or sulfur;

B is selected from the group consisting of O, NR², S(O)_(r), C═O, C═S, and C═NOR³,

p is 0 or 1;

q, at each occurrence, independently is 0 or 1;

r is 0, 1, or 2;

R², at each occurrence, independently is selected from the group consisting of:

-   -   a) hydrogen, b) S(O)_(r)R⁴, c) formyl, d) C₁₋₈ alkyl, e) C₂₋₈         alkenyl, f) C₂₋₈ alkynyl, g) C₁₋₈ alkoxy, h) C₁₋₈ alkylthio, i)         C₁₋₈ acyl, j) saturated, unsaturated, or aromatic C₃₋₈         carbocycle, and k) saturated, unsaturated, or aromatic 5-10         membered heterocycle containing one or more heteroatoms selected         from the group consisting of nitrogen, oxygen, and sulfur,         -   wherein any of d)-k) optionally is substituted with one or             more moieties selected from the group consisting of             carbonyl, aryl, substituted aryl, heteroaryl, substituted             heteroaryl, F, Cl, Br, I, CN, NO₂, —NR³R³, OR³, —S(O)_(r)R⁴,             —S(O)_(r)NR³R³, —C(O)R³, —C(O)OR³, —OC(O)R³, —C(O)NR³R³, and             —OC(O)NR³R³;

alternatively, two R² groups, taken together with the atom to which they are bonded, form i) 5-8 membered saturated or unsaturated carbocycle, or ii) 5-8 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur,

-   -   wherein i)-ii) optionally is substituted with one or more         moieties selected from the group consisting of carbonyl, F, Cl,         Br, I, CN, NO₂, —NR³R³, —OR³, —S(O)_(r)R⁴, NR³R³, C(OR³,         —C(O)OR³, —OC(O)R³, —C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ acyl, aryl,         substituted aryl, heteroaryl, and substituted heteroaryl;

R³, at each occurrence, independently is selected from the group consisting of:

-   -   a) hydrogen, b) C₁₋₈ alkyl, c) C₂₋₈ alkenyl, d) C₂₋₈ alkynyl, e)         C₁₋₈ acyl, f) saturated, unsaturated, or aromatic C₃₋₈         carbocycle, and g) saturated, unsaturated, or aromatic 5-10         membered heterocycle containing one or more heteroatoms selected         from the group consisting of nitrogen, oxygen, and sulfur,         -   wherein any of b)-h) optionally is substituted with one or             more moieties selected from the group consisting of             carbonyl, F, Cl, Br, I, CN, NO₂, —NR⁶R⁶, —OR⁶, —S(O)_(r)R⁶,             —S(O)_(r)NR⁶R⁶, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁶,             —OC(O)NR⁶R⁶, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl,             and substituted heteroaryl;

alternatively, two R³groups, taken together with the atom to which they are bonded, form i) a 5-7 membered saturated or unsaturated carbocycle, or ii) a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur,

-   -   wherein i)-ii) optionally is substituted with one or more         moieties selected from the group consisting of carbonyl, F, Cl,         Br, I, CN, NO₂, —NR⁶R⁶, —OR⁶, S(O)_(r)R⁶, —S(O)_(r)NR⁶R⁶,         —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁶, —OC(O)NR⁶R⁶, C₁₋₆ acyl,         aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R⁴ is selected from the group consisting of:

-   -   a) hydrogen, b) —NR³R³, c) —NR³OR³, d) —NR³NR³R³ e)         —NHC(O)R³, f) —C(O)NR³R³, g) —N₃, h) C₁₋₈ alkyl, i) C₂₋₈         alkenyl, j) C₂₋₈ alkynyl, k) saturated, unsaturated, or aromatic         C₃₋₈ carbocycle, and 1) saturated, unsaturated, or aromatic 5-10         membered heterocycle containing one or more heteroatoms selected         from the group consisting of nitrogen, oxygen, and sulfur,         -   wherein any of h)-l) optionally is substituted with one or             more moieties selected from the group consisting of             carbonyl, F, Cl, Br, I, CN, NO₂, —NR³R³, —OR³, —SR³,             —S(O)_(r)R⁵, —S(O)_(r)NR³R³, —C(O)R³, —C(O)OR³, —OC(O)R³,             —C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆             alkynyl, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, and             substituted heteroaryl;

R⁵ is selected from the group consisting of:

-   -   a) hydrogen, b) —NR³R³, c) —NR³OR³, d) —NR³NR³R³ e)         —NHC(O)R³, f) —C(O)NR³R³, g) —N₃, h) C₁₋₈ alkyl, i) C₂₋₈         alkenyl, j) C₂₋₈ alkynyl, k) saturated, unsaturated, or aromatic         C₃₋₈ carbocycle, and 1) saturated, unsaturated, or aromatic 5-10         membered heterocycle containing one or more heteroatoms selected         from the group consisting of nitrogen, oxygen, and sulfur,         -   wherein any of h) —1) optionally is substituted with one or             more moieties selected from the group consisting of F, Cl,             Br, I, CN, NO₂, —NR³R³, —OR³, —SR³—C(O)R³, —C(O)OR³,             —OC(O)R³, —C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ alkyl, C₁₋₆ alkenyl,             C₁₋₆ alkynyl, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl,             and substituted heteroaryl; and

R⁶, at each occurrence, independently is selected from the group consisting of: hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

alternatively, two R⁶ groups taken together are —(CH₂)_(s)—, wherein s is 1,2,3,4, or 5;

D-E is selected from the group consisting of:

E is selected from the group consisting of:

d) 5-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R¹³ groups;

e) C₅₋₁₀ saturated, unsaturated, or aromatic carbocycle, optionally substituted with one or more R¹³ groups;

f) C₁₋₈ alkyl,

g) C₂₋₈ alkenyl,

h) C₃₋₈ alkynyl,

i) C₁₋₈ alkoxy,

j) C₁₋₈ alkylthio,

k) C₁₋₈ acyl,

l) S(O)_(r)R⁵; and

m) hydrogen,

n) a β-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, wherein the β-carbolin-3-yl, or indolizinyl optionally is substituted with one to three R³⁰ groups;

wherein any of f)-k) optionally is substituted with

-   -   i) one or more R¹³ groups;     -   ii) 5-6 membered saturated, unsaturated, or aromatic heterocycle         containing one or more heteroatoms selected from the group         consisting of nitrogen, oxygen, and sulfur, and optionally         substituted with one or more R¹³ groups; or     -   iii) C₅₋₁₀ saturated, unsaturated, or aromatic carbocycle,         optionally substituted with one or more R¹³ groups;

R⁷ is selected from the group consisting of:

-   -   a) hydrogen, b) carbonyl, c) formyl, d) F, e) Cl, f) Br, g)         I, h) CN, i) NO₂, j) OR³, k) —S(O)_(r)R⁵, l) —S(O)_(i)N═R², m)         —C(O)R², n) —C(O)OR³, o) —OC(O)R², p) —C(O)NR²R², q)         —OC(O)NR²R², r) —C(═NR¹²)R², s) —C(R²)(R²)OR³, t)         —C(R²)(R²)OC(O)R², u) —C(R²)(OR³)(CH₂)_(r)NR²R², v) —NR²R², w)         —NR²OR³ x) —N(R²)C(O)R², y) —N(R²)C(O)OR³, z) —N(R²)C(O)NR²R²,         aa) —N(R²)S(O)_(r)R², bb) —C(OR⁶)(OR⁶)R², cc) —C(R²)(R³)NR²R²,         dd) —C(R²)(R³)NR²R², ee) ═NR¹², ff) —C(S)NR²R², gg)         —N(R²)C(S)R², hh) —OC(S)NR²R², ii) —N(R²)C(S)OR³, jj)         —N(R²)C(S)NR²R², kk) —SC(O)R², ll) C₁₋₈ alkyl, mm) C₂₋₈ alkenyl,         nn) C₂₋₈ alkynyl, oo) C₁₋₈ alkoxy, pp) C₁₋₈ alkylthio, qq) C₁₋₈         acyl, m) saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle,         and ss) saturated, unsaturated, or aromatic 5-10 membered         heterocycle containing one or more heteroatoms selected from the         group consisting of nitrogen, oxygen, and sulfur,         -   wherein any of ll)-ss) optionally is substituted with one or             more moieties selected from the group consisting of:         -   carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³; —S(O)_(r)R⁵;             —S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²; —C(O)NR²R²;             —OC(O)NR²R²; —C(═NR¹⁰)R²; —C(R²)(R²)OR³; —C(R²)(R²)OC(O)R²;             —C(R²)(OR³)(CH₂)_(r)NR²R²; —NR²R²; —NR²OR²; —NR²C(O)R²;             —NR²C(O)OR³; —NR²C(O)NR²R²; —NR²S(O)_(r)R⁵; —C(OR⁶)(OR⁶)R²;             —C(R²)(R³)NR²R²; —C(R²)(R³)NR²R²; ═NR²; —C(S)NR²R²;             —NR²C(S)R²; —OC(S)NR²R²; —NR²C(S)OR³; —NR²C(S)NR²R²;             —SC(O)R²; C₂₋₅ alkenyl; C₂₋₅ alkynyl; C₁₋₈ alkoxy; C₁₋₈             alkylthio; C₁₋₈ acyl; saturated, unsaturated, or aromatic             C₅₋₁₀ carbocycle, optionally substituted with one or more R⁸             groups; and saturated, unsaturated, or aromatic 5-10             membered heterocycle containing one or more heteroatoms             selected from the group consisting of nitrogen, oxygen, and             sulfur, and optionally substituted with one or more R⁸             groups;

R⁸ is selected from the group consisting of:

-   -   hydrogen; F; Cl; Br; I; CN; NO₂; OR⁶; aryl; substituted aryl;         heteroaryl; substituted heteroaryl; and C₁₋₆ alkyl, optionally         substituted with one or more moieties selected from the group         consisting of aryl, substituted aryl, heteroaryl, substituted         heteroaryl, F, Cl, Br, I, CN, NO₂, and OR⁶

alternatively, R⁷ and R⁸ taken together are —O(CH₂)_(r)O—;

R⁹, at each occurrence, independently is selected from the group consisting of:

-   -   hydrogen, F, Cl, Br, I, CN, OR³, NO₂, —NR²R², C₁₋₆ alkyl, C₁₋₆         acyl, and C₁₋₆ alkoxy;

R¹⁰ is selected from the group consisting of:

-   -   a) saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle,     -   b) saturated, unsaturated, or aromatic 5-10 membered heterocycle         containing one or more heteroatoms selected from the group         consisting of nitrogen, oxygen, and sulfur,     -   c) —X—C₁₋₆ alkyl-saturated, unsaturated, or aromatic 5-10         membered heterocycle containing one or more heteroatoms selected         from the group consisting of nitrogen, oxygen, and sulfur,         -   wherein X is O or NR³,     -   d) saturated, unsaturated, or aromatic 10-membered bicyclic ring         system optionally containing one or more heteroatoms selected         from the group consisting of nitrogen, oxygen, and sulfur,     -   e) saturated, unsaturated, or aromatic 13-membered tricyclic         ring system optionally containing one or more heteroatoms         selected from the group consisting of nitrogen, oxygen, and         sulfur,     -   ll) —C(O)CH₃, and mm) R⁹,     -   wherein any of a)-kk) optionally is substituted with one or more         R¹³ groups;

alternatively, R¹⁰ and one R⁹ group taken together is

alternatively, R¹⁰ and one R⁹ group, taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R¹³ groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R¹³ groups;

R¹¹ at each occurrence, independently is selected from the group consisting of: hydrogen; an electron-withdrawing group; aryl; substituted aryl; heteroaryl; substituted heteroaryl; and C₁₋₆ alkyl, optionally substituted with F, Cl, or Br;

alternatively, any R¹¹ and R⁸, taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R¹ groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R¹³ groups;

alternatively, any R¹¹ and R⁸, taken together with the atoms to which they are bonded, form —(CH₂)_(k)— or a 5-, 6-, or 7-membered ring having the formula:

-   -   wherein         -   u is 2, 3, 4, or 5;

R¹² is selected from the group consisting of:

-   -   —NR²R², —OR³, —OC(O)R², —OC(O)OR³, —NR²C(O)R², —NR²C(O)NR²R²,         —NR²C(S)NR²R², and —NR²C(═NR²)NR²R²;

R¹³, at each occurrence, independently is selected from the group consisting of:

-   -   a) hydrogen, b) carbonyl, c) formyl d) F, e) Cl, f) Br, g) I, h)         CN, i) NO₂, j) OR³, k) —S(O)_(r)R⁵, l) —S(O)_(r)N═R³, m)         —C(O)R², n) —C(O)OR³, o) —OC(O)R², p) —C(O)NR²R², q)         —OC(O)NR²R², r) —C(═NR²)R², s) —C(R²)(R²)OR³, t)         —C(R²)(R²)OC(O)R², u) —C(R²)(OR³)(CH₂)_(r)NR²R², v) —NR²R², w)         —NR²OR³, x) —N(R²)C(O)R², y) —N(R²)C(O)OR³, z) —N(R²)C(O)NR²R²,         aa) —N(R²)S(O)_(r)R⁵, bb) —C(OR⁶)(OR⁶)R², cc) —C(R²)(R³)NR²R²,         dd) —C(R²)(R³)NR²R², ee) ═NR², ff) —C(S)NR²R², gg) —N(R²)C(S)R²,         hh) —OC(S)NR²R², ii) —N(R²)C(S)OR³, jj) —N(R²)C(S)NR²R², kk)         —SC(O)R², ll) C₁₋₈ alkyl, mm) C₂₋₈ alkenyl, nn) C₂₋₈ alkynyl,         oo) C₁₋₈ alkoxy, pp) C₁₋₈ alkylthio, qq) C₁₋₈ acyl, m)         saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle, ss)         saturated, unsaturated, or aromatic 5-10 membered heterocycle         containing one or more heteroatoms selected from the group         consisting of nitrogen, oxygen, and sulfur, tt) saturated,         unsaturated, or aromatic 10-membered bicyclic ring system         optionally containing one or more heteroatoms selected from the         group consisting of nitrogen, oxygen, and sulfur, and uu)         saturated, unsaturated, or aromatic 13-membered tricyclic ring         system optionally containing one or more heteroatoms selected         from the group consisting of nitrogen, oxygen, and sulfur,         -   wherein any of ll)-uu) optionally is substituted with one or             more moieties selected from the group consisting of:             carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³; —S(O)_(r)R⁵;             —S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²; —C(O)NR²R²;             —OC(O)NR²R²; —C(═NR²)R²; —C(R²)(R²)OR³; —C(R²)(R²)OC(O)R²;             —C(R²)(OR³)(CH₂)_(r)NR²R²; —NR²R²; —NR²OR³; —NR²C(O)R²;             —NR²C(O)OR³; —NR²C(O)NR²R²; —NR²S(O)_(r)R⁵; —C(OR⁶)(OR⁶)R²;             —C(R²)(R³)NR²R²; —C(R²)(R³)NR²R²; ═NR²; —C(S)NR²R²;             —NR²C(S)R²; —OC(S)NR²R²; —NR²C(S)OR³; —NR²C(S)NR²R²;             —SC(O)R²; C₁₋₈ alkyl, C₂₋₈ alkenyl; C₂₋₈ alkynyl; C₁₋₈             alkoxy; C₁₋₈ alkylthio; C₁₋₈ acyl; saturated, unsaturated,             or aromatic C₃₋₁₀ carbocycle optionally substituted with one             or more R⁷ groups; and saturated, unsaturated, or aromatic             3-10 membered heterocycle containing one or more heteroatoms             selected from the group consisting of nitrogen, oxygen, and             sulfur, and substituted with one or more R⁷ groups;

A′ is CH, N, S, or O;

B′ is O, S, or NR²;

D′ is an unsaturated 4-atom linker containing one nitrogen atom and three carbon atoms, which forms a pyridyl ring fused with the heteroaryl moiety;

E′ is O, NR⁵¹ or S(O)_(r);

G′ is —CH₂—, —CH₂CH₂—, —CH₂(OH)CH₂—, —C(O)—, or —CH₂CH₂CH₂—;

J′ is —S(O)_(f)—, —O—, or —NR³⁶—;

K′ is CH₂, O, S, or NR²;

R³⁰ is selected from the group consisting of:

-   -   a) carbonyl, b) formyl, c) F, d) Cl, e) Br, f) CN, g) —OR³, h)         —SR³, i) —CF₃, j) —NO₂ k) —NR²R², l) —NR³⁸R³⁸, m)     -   n) C₁₋₆ alkyl, o) C₂₋₆ alkenyl, p) C₂₋₆ alkynyl, q) C₁₋₆         alkoxy, r) —C(O)—C₁₋₆ alkyl, s) C₁₋₆ alkylthio, t) C₁₋₆ acyl, u)         C₂₋₈ alkenylphenyl, v) aryl, and w) heteroaryl, wherein any of         n)-w) optionally is substituted with one or more R³⁹ groups;

R³¹, at each occurrence, independently is selected from the group consisting of:

-   -   a) hydrogen, b) carbonyl, c) F, d) Cl, e) Br, f) —CN, g)         formyl, h) —NO₂, i) —OR³, j) —NR²R², k) aryl, l) substituted         aryl, m) heteroaryl, n) substituted aryl, o) C₁₋₆ alkyl, p) C₂₋₆         alkenyl, q) C₂₋₆ alkynyl, r) C₁₋₆ alkylthio, s) C₁₋₆ acyl, t)         C₁₋₆ alkoxy, and u) —C(O)C₁₋₆ alkoxy,     -   wherein any of o)-u) optionally is substituted with one or more         moieties from the group consisting of:         -   —N(phenyl)(CH₂CH₂OH), —OCH(CH₃)(OCH₂CH₃),             —O-phenyl-[para-NHC(O)CH₃], and R¹³;

R³², at each occurrence, independently is selected from the group consisting of:

-   -   a) hydrogen, b) carbonyl, c) formyl, d) —OR⁴³, e) —NR⁴⁴R⁴⁴, f)         —S(O)_(r)R⁴⁷, g) —S(O)_(r)NR⁴⁴R⁴⁴, h) aryl, i) substituted         aryl, j) heteroaryl, k) substituted heteroaryl, l) C₁₋₆         alkyl, m) C₂₋₆ alkenyl, n) C₂₋₆ alkynylo) C₁₋₆ alkylthio, p)         C₁₋₆ acyl, q) C₁₋₆ alkoxy, r) —C(O)—C₁₋₆ alkoxy,     -   wherein any of n)-w) optionally is substituted with one or more         moieties from the group consisting of:         -   —N(phenyl)(CH₂CH₂OH), —OCH(CH₃)(OCH₂CH₃),         -   —O-phenyl-[para-NHC(O)CH₃] and R¹³;

R³³ is hydrogen, F, Cl, Br, C₁₋₆ alkyl, or C₁₋₆ alkyl-aryl;

R³⁴ is hydrogen or CH₃;

R³⁵ is selected from the group consisting of:

-   -   hydrogen, —OH, —CH₃, —OCH₃, —NHC(O)OR², —NHC(O)CH₂OR³,         —C(O)O—C₁₋₆ alkyl, —CH₂OH, —NHOCH₃, —C(O)O—C₁₋₆ alkyl, —C(O)CH₃,         —CH₂C(O)CH₃,

alternatively, R³⁴ and R³⁵ taken together are a carbonyl, ═NR⁴⁸, or

R³⁶ is selected from the group consisting of:

-   -   —C(O)OR³, —C(O)C(R⁵⁰)(R⁵⁰(OR³), —C(O)R², —SO₂R⁴,         —C(O)(CH₂)₂C(O)CH₃, —C(O)CH₂OH, —(CH₂)₂R², —C(O)CH₂OC(O)R²,         —CH₂CN, —CH₂CHF₂, —SO₂NR²R², —NHC(O)CH₂N(CH₃)₂,

R³⁷ is selected from the group consisting of:

-   -   —C(O)CH₃, —C(O)H, —C(O)CHCl₂, —C(O)CH₂OH, —SO₂CH₃,         —C(O)CH₂OC(O)CH₃, —C(O)CHF₂, —C(O)CH₂OC(O)H, —C(O)CH₂OCH₂—C≡CH,         —C(O)CH₂OCH₂C₆H₅,

R³⁸, at each occurrence, independently is selected from the group consisting of:

-   -   hydrogen, formyl, C₁₋₄ alkyl, C₁₋₄ acyl, aryl, C₃₋₆ cycloalkyl,         —P(O)(OR³)(OR³), and —SO₂R⁴;

alternatively, two R³⁸ groups taken together with the atom to which they are bonded form a 5- or 6-membered saturated heterocyclic group containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with phenyl, pyrimidyl, C₁₋₃ alkyl, or C₁₋₃ acyl;

R³⁹ is selected from the group consisting of:

-   -   a) carbonyl, b) formyl, c) F, d) Cl, e) Br, f) I, g) CN, h)         —OR³, i) —SR³, j) —CF₃, k) —NO₂, l) —NR²R², m) —C(O)NR²R², n)         —NR²R², o) —NR²(SO₂R⁶), p) —SO₂NR²R², q) —S(O)_(r)R⁶, r)         —CH═N—R⁴, s) —CH(OH)SO₃R⁴¹, t) C₁₋₆ alkyl, u) C₂₋₆ alkenyl, v)         C₂₋₆ alkynyl, w) C₁₋₆ alkoxy, x) —C(O)—C₁₋₆ alkyl, y) C-6         alkylthio, z) C₁₋₆ acyl, aa) C₂₋₈ alkenylphenyl, bb) aryl,         and cc) heteroaryl,         -   wherein any of s)-bb) optionally is substituted with —OH,             —N₃, C₁₋₅ alkoxy, C₁₋₅ acyl, —NR²R², —SR⁴², —OSO₂R⁶, or

R⁴⁰ is —OH, —OCH₂-aryl, —NHC(O)NH₂, —NHC(S)NH₂, or —NHC(═NH)NR²R²;

R⁴¹ is hydrogen or a sodium ion;

R⁴² is selected from the group consisting of:

R⁴³ is selected from the group consisting of:

-   -   a) C₁₋₈ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, d) heteroaryl, e)         pyridyl, and f)     -   wherein         -   any of a)-f) optionally is substituted with one or more R¹³             groups, and L′ is O, CH₂, or NR²;

R⁴⁴, at each occurrence, independently is selected from the group consisting of:

-   -   a) hydrogen, b) C₃₋₆ cycloalkyl, c) C₁₋₆ acyl, d) C₁₋₈ alkyl, e)         C₁₋₆ alkoxy, f) heteroaryl, g) aryl,     -   wherein         -   any of b)-g) optionally is substituted with one or more R¹³             groups, or         -   L′ is O, CH₂, or NR²;

R⁴⁵ is —OH, C₁₋₄ alkoxy, or —NR²R²;

R⁴⁶ is hydrogen or a C₁₋₈ alkyl group optionally substituted with one or moieties selected from the group consisting of indolyl, —OR³, —SR³, imidazolyl, C₁₋₈ alkylthio, —NR²R², and aryl,

-   -   wherein the aryl group optionally is substituted with OH,         —C(O)NH₂, —CO₂H, or —C(═NH)NH₂;

R⁴⁷ is selected from the group consisting of:

-   -   a) C₁₋₁₆ alkyl, b) C₂₋₁₆ alkenyl, c) aryl, and d) heteroaryl,         wherein any of a)-d) optionally is substituted with one or more         R¹³ groups;

R⁴⁸ is selected from the group consisting of:

-   -   —OH, —OCH₃, —NH₂, —OC(O)OCH₃, —OC(O)CH₂OC(O)CH₃, —O(CH₂)₂OH,         —OC(O)CH₂OCH₂C₆H₅, —O(CH₂)₂OCH₂OCH₃, and —OCH₂OCH₃;

R⁴⁹ is selected from the group consisting of:

-   -   hydrogen, —CH₂OH, and —CH₂OCH₂OCH₃;

R⁵⁰, at each occurrence, independently is hydrogen or CH₃;

alternatively, two R⁵⁰ groups taken together with the carbon atom to which each is bonded are —CH₂CH₂—;

R⁵¹ is selected from the group consisting of:

-   -   a) hydrogen, b) C₁₋₆ alkyl, optionally substituted with one or         more hydroxyl groups, halogens, or —CN, c) —(CH₂)_(s)-aryl, d)         —CO₂R⁵², e) —COR⁵³, f) —C(O)(CH₂)C(O)R⁵², g) —S(O)₂—C₁₋₆         alkyl, h) —S(O)₂(CH₂)_(s)-aryl, and i) —(C(O))_(s)-Het;

R⁵² is selected from the group consisting of:

-   -   a) hydrogen, b) C₁₋₆ alkyl, optionally substituted with one or         more hydroxyl groups, halogens, or —CN, c) —(CH₂)_(s)-aryl,         and d) —(CH₂)_(s)—OR⁵⁴;

R⁵³ is selected from the group consisting of:

-   -   a) C₁₋₆ alkyl, optionally substituted with one or more hydroxyl         groups, halogens, or —CN, b) —(CH₂)_(s)-aryl, and c)         —(CH₂)_(s)—OR⁵⁴;

R⁵⁴ is selected from the group consisting of:

-   -   a) hydrogen, b) C₁₋₆ alkyl, c) KCH₂)_(s)-aryl, and d) —C(O)—C₁₋₆         alkyl,         -   wherein the aryl group is selected from the group consisting             of phenyl, pyridyl, and napthyl,             -   wherein each of the phenyl, pyridyl, and napthyl                 optionally is substituted with one or more moieties from                 the group consisting of F, Cl, Br, —CN, —OH, —SH, C₁₋₆                 alkyl, C₁₋₆ alkoxy, and C₁₋₆ alkylthio; and

G is selected from the group consisting of

-   -   a) C₁₋₄ alkyl, b) C₅₋₈ alkyl, c) C₂₋₈ alkenyl, d) C₂₋₈         alkynyl, e) C₁₋₈ alkoxy, f) C₁₋₈ alkylthio, g) C₁₋₈ acyl, h)         saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle, i)         saturated, unsaturated, or aromatic 5-10 membered heterocycle         containing one or more heteroatoms selected from the group         consisting of nitrogen, oxygen, and sulfur,     -   wherein         -   i) a) is substituted with, and         -   ii) any of b)-i) optionally is substituted with one or more             moieties selected from the group consisting of:             -   carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³;                 —S(O)_(r)R⁵; —S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²;                 —C(O)NR²R²; —OC(O)NR²R²; —C(═NR¹²)R²; —C(R²)(R²)OR³;                 —C(R²)(R²)OC(O)R²; —C(R²)(OR³)(CH₂)_(r)NR²R²; —NR²R²;                 —NR²OR³; —NR²C(O)R²; —NR²C(O)OR³; —NR²C(O)NR²R²;                 —NR²S(O)_(r)R⁵; —C(OR)(OR)R²; —C(R²)(R³)NR²R²;                 —C(R²)(R³)NR²R¹²; ═NR²; —C(S)NR²R²; —NR²C(S)R²;                 —OC(S)NR²R²; —NR²C(S)OR³; —NR²C(S)NR²R²; —SC(O)R²; C₂₋₅                 alkenyl; C₂₋₅ alkynyl; C₁₋₈ alkoxy; C₁₋₈ alkylthio; C₁₋₈                 acyl; saturated, unsaturated, or aromatic C₅₋₁₀                 carbocycle, optionally substituted with one or more R¹³                 groups; and saturated, unsaturated, or aromatic 5-10                 membered heterocycle containing one or more heteroatoms                 selected from the group consisting of nitrogen, oxygen,                 and sulfur, and optionally substituted with one or more                 R¹³ groups;

t, at each occurrence, independently is 0, 1, 2, or 3;

v is 0, 1, 2, 3, 4, 5, or 6;

K′ is O, NR², or S(O)_(r);

R⁵⁵, at each occurrence, independently is hydrogen, —CH₂OH, or C₁₋₄ alkyl;

alternatively, two R⁵⁵ groups taken together are a carbonyl group;

R¹⁴ is selected from the group consisting of:

-   -   a) hydrogen, b) C₁₋₆-alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆ alkynyl, e)         —C(O)—R³, f) —C(O)—C₁₋₆ alkyl-R³, g) —C(O)—C₂₋₆ alkenyl-R³, h)         —C(O)—C₂₋₆ alkynyl-R³, i) —C₁₋₆ alkyl-J-R³, j) —C₂₋₆         alkenyl-J-R³; and k) —C₂₋₆ alkynyl-J-R³;         -   wherein             -   (i) any of b)-d) optionally is substituted with one or                 more substituents selected from the group consisting of:                 -   F, Cl, Br, I, aryl, substituted aryl, heteroaryl,                     substituted heteroaryl, —OR³, —O—C₁₋₆ alkyl-R²,                     —O—C₂₋₆ alkenyl-R², —O—C₂₋₆ alkynyl-R², and —NR²R²;                     and             -   (ii) J is selected from the group consisting of:                 -   —OC(O)—, —OC(O)O—, —OC(O)NR²—, —C(O)NR²—, —NR²C(O)—,                     —NR²C(O)O, —NR²C(O)NR²—, —NR²C(NH)NR—, and S(O)_(r);                     and

R¹⁵ is selected from the group consisting of:

-   -   hydrogen; C₁₋₁₀ alkyl, optionally substituted with one or more         R¹³ groups; C₁₋₆ acyl, optionally substituted with one or more         R¹³groups; aryl; substituted aryl; heteroaryl; substituted         heteroaryl; arylalkyl; substituted arylalkyl; and a macrolide;         -   wherein the macrolide is selected from the group consisting             of:             and pharmaceutically acceptable salts, esters and prodrugs             thereof, wherein

R¹⁷ is selected from the group consisting of:

-   -   hydrogen, hydroxy protecting group, R³, and —V—W—R¹³,         -   wherein             -   V is —C(O), —C(O)O—, —C(O)NR²—, or absent, and             -   W is C₁₋₆ alkyl, or absent;

alternatively R¹⁷ and R⁴, taken together with the atoms to which they are bonded, form:

Q is selected from the group consisting of:

-   -   —NR²CH₂—, —CH₂—NR²—, —C(O)—, —C(═NR²)—, —C(═NOR³)—,         —C(═N—NR²R²)—, —CH(OR³)—, and —CH(NR²R²)—;

R¹⁸ is selected from the group consisting of:

-   -   i) C₁₋₆ alkyl, ii) C₂₋₆ alkenyl, and iii) C₂₋₆ alkynyl;         -   wherein any of i) —11i) optionally is substituted with one             or more moieties selected from the group consisting of —OR³,             aryl, substituted aryl, heteroaryl, and substituted             heteroaryl;

R¹⁹ is selected from the group consisting of:

-   -   a) —OR⁷, b) C-6 alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆ alkynyl, e)         —NR²R², f) —C(O)R³,     -   g) —C(O)—C₁₋₆ alkyl-R³, h) —C(O)—C₂₋₆ alkenyl-R³, and i)         —C(O)—C₂— alkynyl-R¹³, wherein any of b)-d) optionally is         substituted with one or more R¹³ groups;

alternatively, R¹⁴ and R¹⁹, taken together with the atoms to which they are bonded, form:

-   -   wherein         -   L is CH or N, and         -   R²³ is —OR³, or R³;

R²⁰ is —OR¹⁷

alternatively, R¹⁹ and R²⁰, taken together with the atoms to which they are bonded, form a 5-membered ring by attachment to each other through a linker selected from the group consisting of:

-   -   —OC(R²)(R²)O—, —OC(O)O—, —OC(O)NR²—, —NR²C(O)O—, —OC(O)NOR³—,         —N(OR³)C(O)Q, —OC(O)N—NR²R²—, —N(NR²R²)C(O)O, —OC(O)CHR²—,         —CHR²C(O)O—, —OC(S)O—, —OC(S)NR²—, —NR²C(S)O—, —OC(S)NOR²—,         —N(OR³)C(S)O—, —OC(S)N—NR²R²—, —N(NR²R²)C(S)O—, —OC(S)CHR²—, and         —CHR²C(S)O—;

alternatively, Q, R¹⁹, and R²⁰, taken together with the atoms to which they are bonded, form:

-   -   wherein         -   M is O or NR²;

R²¹ is selected from the group consisting of:

-   -   hydrogen, F, Cl, Br, I, and C₁₋₆ alkyl;

R²², at each occurrence, independently is selected from the group consisting of:

-   -   hydrogen, —OR³, —O-hydroxy protecting group, —O—C₁₋₆         alkyl-J-R¹³, —O—C₂₋₆ alkenyl-J-R³, —O—C₁₋₆alkynyl-J-R¹³, and         —NR²R²;

alternatively, two R²² groups taken together are ═O, ═N—OR³, or ═N—NR²R²; and

-   -   R², R³, R¹³, R¹⁴, and J are as described hereinabove.

Examples of:

include, but are not limited to, thiophene, furan, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 4,5,-dihydrooxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1-tetrazol-5-yl, 2-tetrazol-5-yl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazolidine-2,4-dione, oxazolidine-2,4-dione, imidazolidine-2,4-dione, oxazolidin-2-one, thiazolidin-2-one, 3H-oxazol-2-one, 1,3-dihydro-imidazol-2-one, 1,3-dihydro-imidazole-2-thione, 2-thioxo-imidazolidin-4-one, and 4-thioxo-imidazolidin-2-one.

In certain embodiments, the invention provides compounds having the formula:

-   -   wherein         -   A, at each occurrence, independently is carbon or nitrogen,             provided at least one A is carbon, and         -   p, q, B, D, E, and G are as defined hereinabove.

Other embodiments of the invention include compounds having the formula:

wherein

-   -   Y is oxygen or sulfur,     -   A, at each occurrence, independently is carbon or nitrogen, and     -   p, q, B, D, E, and G are as defined hereinabove.

In other embodiments, the invention provides compounds having the formula:

-   -   wherein p, q, A, B, E, and G are as defined hereinabove.

Features of these embodiments include compounds having the formula:

-   -   wherein A, E, and G are as defined hereinabove.

In some embodiments, the invention provides compounds having the formula:

-   -   wherein p, q, A, E, and G are as defined hereinabove.

Features of these embodiments include compounds having the formula:

-   -   wherein A, E, and G are as defined hereinabove.

In certain embodiments, E has the formula:

-   -   wherein R⁹ and R¹⁰, at each occurrence, are as defined         hereinabove. Features of this embodiment include compounds         wherein E has the formula:

Other features of this embodiment include compounds wherein R¹⁰ has the formula:

-   -   wherein K is selected from the group consisting of O, NR², and         S(O)_(r), and x is 0, 1, 2, or 3.

In certain features of this embodiment, K is oxygen, and in other features, t is 1.

Still other features of this embodiment include compounds wherein R¹⁰ is —C(O)CH₃.

Yet another feature of this embodiment includes compounds wherein R¹⁰ has the formula:

-   -   wherein R² and R⁷ are as defined hereinabove.

Certain other features of this embodiment include compounds wherein R² is —C(O)—CH₂—OH. In other features, R⁷ is hydrogen.

In other embodiments according to the invention, in the foregoing compounds, G has the formula:

wherein R¹⁵ is a macrolide.

In other embodiments of the invention, G has the formula selected from the group consisting of:

and R¹⁵ is selected from the group consisting of:

In another embodiments according to the invention, in the foregoing compounds, G has the formula:

wherein n is 1, 2, 3 or 4.

In still other embodiments, the invention provides compounds having the formula:

wherein G is as described hereinabove. Features of this embodiment include compounds wherein G is selected from the group consisting of:

Other embodiments of the invention include compounds having the formula selected from:

or a pharmaceutically acceptable salt, ester, or prodrug thereof.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the foregoing compounds and a pharmaceutically acceptable carrier. In yet another aspect, the invention provides a method for treating a microbial infection, a fungal infection, a viral infection, a parasitic disease, a proliferative disease, an inflammatory disease, or a gastrointestinal motility disorder in a mammal by administering effective amounts of the compounds of the invention or pharmaceutical compositions of the invention, for example, via oral, parenteral or topical routes. In still another aspect, the invention provides methods for synthesizing any one of the foregoing compounds. In another aspect, the invention provides a medical device, for example, a medical stent, which contains or is coated with one or more of the foregoing compounds.

In another embodiment, the invention further provides a family of hybrid antibiotics comprising a heterocyclic side-chain linked via a heterocyclic linker to at least a portion of a macrolide-based antibiotic. Exemplary heterocyclic side-chains, heterocylic linkers, and macrolides useful in the synthesis of the hybrid antibiotics include, but are not limited to, the chemical moieties shown below:

For the above heterocyclic linkers, it should be understood that “O” and “M” are included to depict the orientation of the heterocyclic linker with respect to the other structures that define the compounds of the invention. More specifically, “O” denotes the portion of the compound that includes the heterocyclic side-chain moiety, and “M” denotes the portion of the compound that includes the macrolide moiety.

An exemplary scheme showing the linkage of a heterocyclic side-chain to a macrolide via a heterocyclic linker is shown below, where n can be 1, 2, 3, or 4:

The various heterocyclic side-chains may be linked via the heterocyclic linkers to the macrolides using conventional chemistries known in the art, such as those discussed below. By using the various combinations of chemical moieties provided, the skilled artisan may synthesize one or more of the exemplary compounds listed in Table 1. For each set of examples, the four lower case letter designations denote three compounds where n=1, 2, 3, or 4. For example, as a guide to the following table, compound E1a is the n=1 variant of the structure shown on the same row of the table. Compound E1b is the n=2 derivative, compound E1c is the n=3 derivative, and E1d is the n=4 derivative. TABLE 1 Example O Group H Group M Group E1a-d O1 H1 M1 E2a-d O1 H2 M1 E3a-d O1 H3 M1 E4a-d O1 H4 M1 E5a-d O1 H5 M1 E6a-d O1 H6 M1 E7a-d O1 H7 M1 E8a-d O1 H8 M1 E9a-d O1 H9 M1 E10a-d O2 H1 M1 E11a-d O2 H2 M1 E12a-d O2 H3 M1 E13a-d O2 H4 M1 E14a-d O2 H5 M1 E15a-d O2 H6 M1 E16a-d O2 H7 M1 E17a-d O2 H8 M1 E18a-d O2 H9 M1 E19a-d O3 H1 M1 E20a-d O3 H2 M1 E21a-d O3 H3 M1 E22a-d O3 H4 M1 E23a-d O3 H5 M1 E24a-d O3 H6 M1 E25a-d O3 H7 M1 E26a-d O3 H8 M1 E27a-d O3 H9 M1 E28a-d O4 H1 M1 E29a-d O4 H2 M1 E30a-d O4 H3 M1 E31a-d O4 H4 M1 E32a-d O4 H5 M1 E33a-d O4 H6 M1 E34a-d O4 H7 M1 E35a-d O4 H8 M1 E36a-d O4 H9 M1 E37a-d O5 H1 M1 E38a-d O5 H2 M1 E39a-d O5 H3 M1 E40a-d O5 H4 M1 E41a-d O5 H5 M1 E42a-d O5 H6 M1 E43a-d O5 H7 M1 E44a-d O5 H8 M1 E45a-d O5 H9 M1 E46a-d O6 H1 M1 E47a-d O6 H2 M1 E48a-d O6 H3 M1 E49a-d O6 H4 M1 E50a-d O6 H5 M1 E51a-d O6 H6 M1 E52a-d O6 H7 M1 E53a-d O6 H8 M1 E54a-d O6 H9 M1 E55a-d O7 H1 M1 E56a-d O7 H2 M1 E57a-d O7 H3 M1 E58a-d O7 H4 M1 E59a-d O7 H5 M1 E60a-d O7 H6 M1 E61a-d O7 H7 M1 E62a-d O7 H8 M1 E63a-d O7 H9 M1 E64a-d O8 H1 M1 E65a-d O8 H2 M1 E66a-d O8 H3 M1 E67a-d O8 H4 M1 E68a-d O8 H5 M1 E69a-d O8 H6 M1 E70a-d O8 H7 M1 E71a-d O8 H8 M1 E72a-d O8 H9 M1 E73a-d O9 H1 M1 E74a-d O9 H2 M1 E75a-d O9 H3 M1 E76a-d O9 H4 M1 E77a-d O9 H5 M1 E78a-d O9 H6 M1 E79a-d O9 H7 M1 E80a-d O9 H8 M1 E81a-d O9 H9 M1 E82a-d O10 H1 M1 E83a-d O10 H2 M1 E84a-d O10 H3 M1 E85a-d O10 H4 M1 E86a-d O10 H5 M1 E87a-d O10 H6 M1 E88a-d O10 H7 M1 E89a-d O10 H8 M1 E90a-d O10 H9 M1 E91a-d O11 H1 M1 E92a-d O11 H2 M1 E93a-d O11 H3 M1 E94a-d O11 H4 M1 E95a-d O11 H5 M1 E96a-d O11 H6 M1 E97a-d O11 H7 M1 E98a-d O11 H8 M1 E99a-d O11 H9 M1 E100a-d O12 H1 M1 E101a-d O12 H2 M1 E102a-d O12 H3 M1 E103a-d O12 H4 M1 E104a-d O12 H5 M1 E105a-d O12 H6 M1 E106a-d O12 H7 M1 E107a-d O12 H8 M1 E108a-d O12 H9 M1 E109a-d O13 H1 M1 E110a-d O13 H2 M1 E111a-d O13 H3 M1 E112a-d O13 H4 M1 E113a-d O13 H5 M1 E114a-d O13 H6 M1 E115a-d O13 H7 M1 E116a-d O13 H8 M1 E117a-d O13 H9 M1 E118a-d O14 H1 M1 E119a-d O14 H2 M1 E120a-d O14 H3 M1 E121a-d O14 H4 M1 E122a-d O14 H5 M1 E123a-d O14 H6 M1 E124a-d O14 H7 M1 E125a-d O14 H8 M1 E126a-d O14 H9 M1 E127a-d O15 H1 M1 E128a-d O15 H2 M1 E129a-d O15 H3 M1 E130a-d O15 H4 M1 E131a-d O15 H5 M1 E132a-d O15 H6 M1 E133a-d O15 H7 M1 E134a-d O15 H8 M1 E135a-d O15 H9 M1 E136a-d O16 H1 M1 E137a-d O16 H2 M1 E138a-d O16 H3 M1 E139a-d O16 H4 M1 E140a-d O16 H5 M1 E141a-d O16 H6 M1 E142a-d O16 H7 M1 E143a-d O16 H8 M1 E144a-d O16 H9 M1 E145a-d O1 H1 M2 E146a-d O1 H2 M2 E147a-d O1 H3 M2 E148a-d O1 H4 M2 E149a-d O1 H5 M2 E150a-d O1 H6 M2 E151a-d O1 H7 M2 E152a-d O1 H8 M2 E153a-d O1 H9 M2 E154a-d O2 H1 M2 E155a-d O2 H2 M2 E156a-d O2 H3 M2 E157a-d O2 H4 M2 E158a-d O2 H5 M2 E159a-d O2 H6 M2 E160a-d O2 H7 M2 E161a-d O2 H8 M2 E162a-d O2 H9 M2 E163a-d O3 H1 M2 E164a-d O3 H2 M2 E165a-d O3 H3 M2 E166a-d O3 H4 M2 E167a-d O3 H5 M2 E168a-d O3 H6 M2 E169a-d O3 H7 M2 E170a-d O3 H8 M2 E171a-d O3 H9 M2 E172a-d O4 H1 M2 E173a-d O4 H2 M2 E174a-d O4 H3 M2 E175a-d O4 H4 M2 E176a-d O4 H5 M2 E177a-d O4 H6 M2 E178a-d O4 H7 M2 E179a-d O4 H8 M2 E180a-d O4 H9 M2 E181a-d O5 H1 M2 E182a-d O5 H2 M2 E183a-d O5 H3 M2 E184a-d O5 H4 M2 E185a-d O5 H5 M2 E186a-d O5 H6 M2 E187a-d O5 H7 M2 E188a-d O5 H8 M2 E189a-d O5 H9 M2 E190a-d O6 H1 M2 E191a-d O6 H2 M2 E192a-d O6 H3 M2 E193a-d O6 H4 M2 E194a-d O6 H5 M2 E195a-d O6 H6 M2 E196a-d O6 H7 M2 E197a-d O6 H8 M2 E198a-d O6 H9 M2 E199a-d O7 H1 M2 E200a-d O7 H2 M2 E201a-d O7 H3 M2 E202a-d O7 H4 M2 E203a-d O7 H5 M2 E204a-d O7 H6 M2 E205a-d O7 H7 M2 E206a-d O7 H8 M2 E207a-d O7 H9 M2 E208a-d O8 H1 M2 E209a-d O8 H2 M2 E210a-d O8 H3 M2 E211a-d O8 H4 M2 E212a-d O8 H5 M2 E213a-d O8 H6 M2 E214a-d O8 H7 M2 E215a-d O8 H8 M2 E216a-d O8 H9 M2 E217a-d O9 H1 M2 E218a-d O9 H2 M2 E219a-d O9 H3 M2 E220a-d O9 H4 M2 E221a-d O9 H5 M2 E222a-d O9 H6 M2 E223a-d O9 H7 M2 E224a-d O9 H8 M2 E225a-d O9 H9 M2 E226a-d O10 H1 M2 E227a-d O10 H2 M2 E228a-d O10 H3 M2 E229a-d O10 H4 M2 E230a-d O10 H5 M2 E231a-d O10 H6 M2 E232a-d O10 H7 M2 E233a-d O10 H8 M2 E234a-d O10 H9 M2 E235a-d O11 H1 M2 E236a-d O11 H2 M2 E237a-d O11 H3 M2 E238a-d O11 H4 M2 E239a-d O11 H5 M2 E240a-d O11 H6 M2 E241a-d O11 H7 M2 E242a-d O11 H8 M2 E243a-d O11 H9 M2 E244a-d O12 H1 M2 E245a-d O12 H2 M2 E246a-d O12 H3 M2 E247a-d O12 H4 M2 E248a-d O12 H5 M2 E249a-d O12 H6 M2 E250a-d O12 H7 M2 E251a-d O12 H8 M2 E252a-d O12 H9 M2 E253a-d O13 H1 M2 E254a-d O13 H2 M2 E255a-d O13 H3 M2 E256a-d O13 H4 M2 E257a-d O13 H5 M2 E258a-d O13 H6 M2 E259a-d O13 H7 M2 E260a-d O13 H8 M2 E261a-d O13 H9 M2 E262a-d O14 H1 M2 E263a-d O14 H2 M2 E264a-d O14 H3 M2 E265a-d O14 H4 M2 E266a-d O14 H5 M2 E267a-d O14 H6 M2 E268a-d O14 H7 M2 E269a-d O14 H8 M2 E270a-d O14 H9 M2 E271a-d O15 H1 M2 E272a-d O15 H2 M2 E273a-d O15 H3 M2 E274a-d O15 H4 M2 E275a-d O15 H5 M2 E276a-d O15 H6 M2 E277a-d O15 H7 M2 E278a-d O15 H8 M2 E279a-d O15 H9 M2 E280a-d O16 H1 M2 E281a-d O16 H2 M2 E282a-d O16 H3 M2 E283a-d O16 H4 M2 E284a-d O16 H5 M2 E285a-d O16 H6 M2 E286a-d O16 H7 M2 E287a-d O16 H8 M2 E288a-d O16 H9 M2 E289a-d O1 H1 M3 E290a-d O1 H2 M3 E291a-d O1 H3 M3 E292a-d O1 H4 M3 E293a-d O1 H5 M3 E294a-d O1 H6 M3 E295a-d O1 H7 M3 E296a-d O1 H8 M3 E297a-d O1 H9 M3 E298a-d O2 H1 M3 E299a-d O2 H2 M3 E300a-d O2 H3 M3 E301a-d O2 H4 M3 E302a-d O2 H5 M3 E303a-d O2 H6 M3 E304a-d O2 H7 M3 E305a-d O2 H8 M3 E306a-d O2 H9 M3 E307a-d O3 H1 M3 E308a-d O3 H2 M3 E309a-d O3 H3 M3 E310a-d O3 H4 M3 E311a-d O3 H5 M3 E312a-d O3 H6 M3 E313a-d O3 H7 M3 E314a-d O3 H8 M3 E315a-d O3 H9 M3 E316a-d O4 H1 M3 E317a-d O4 H2 M3 E318a-d O4 H3 M3 E319a-d O4 H4 M3 E320a-d O4 H5 M3 E321a-d O4 H6 M3 E322a-d O4 H7 M3 E323a-d O4 H8 M3 E324a-d O4 H9 M3 E325a-d O5 H1 M3 E326a-d O5 H2 M3 E327a-d O5 H3 M3 E328a-d O5 H4 M3 E329a-d O5 H5 M3 E330a-d O5 H6 M3 E331a-d O5 H7 M3 E332a-d O5 H8 M3 E333a-d O5 H9 M3 E334a-d O6 H1 M3 E335a-d O6 H2 M3 E336a-d O6 H3 M3 E337a-d O6 H4 M3 E338a-d O6 H5 M3 E339a-d O6 H6 M3 E340a-d O6 H7 M3 E341a-d O6 H8 M3 E342a-d O6 H9 M3 E343a-d O7 H1 M3 E344a-d O7 H2 M3 E345a-d O7 H3 M3 E346a-d O7 H4 M3 E347a-d O7 H5 M3 E348a-d O7 H6 M3 E349a-d O7 H7 M3 E350a-d O7 H8 M3 E351a-d O7 H9 M3 E352a-d O7 H1 M3 E353a-d O8 H2 M3 E354a-d O8 H3 M3 E355a-d O8 H4 M3 E356a-d O8 H5 M3 E357a-d O8 H6 M3 E358a-d O8 H7 M3 E359a-d O8 H8 M3 E360a-d O8 H9 M3 E361a-d O9 H1 M3 E362a-d O9 H2 M3 E363a-d O9 H3 M3 E364a-d O9 H4 M3 E365a-d O9 H5 M3 E366a-d O9 H6 M3 E367a-d O9 H7 M3 E368a-d O9 H8 M3 E369a-d O9 H9 M3 E370a-d O10 H1 M3 E371a-d O10 H2 M3 E372a-d O10 H3 M3 E373a-d O10 H4 M3 E374a-d O10 H5 M3 E375a-d O10 H6 M3 E376a-d O10 H7 M3 E377a-d O10 H8 M3 E378a-d O10 H9 M3 E379a-d O11 H1 M3 E380a-d O11 H2 M3 E381a-d O11 H3 M3 E382a-d O11 H4 M3 E383a-d O11 H5 M3 E384a-d O11 H6 M3 E385a-d O11 H7 M3 E386a-d O11 H8 M3 E387a-d O11 H9 M3 E388a-d O12 H1 M3 E389a-d O12 H2 M3 E390a-d O12 H3 M3 E391a-d O12 H4 M3 E392a-d O12 H5 M3 E393a-d O12 H6 M3 E394a-d O12 H7 M3 E395a-d O12 H8 M3 E396a-d O12 H9 M3 E397a-d O13 H1 M3 E398a-d O13 H2 M3 E399a-d O13 H3 M3 E400a-d O13 H4 M3 E401a-d O13 H5 M3 E402a-d O13 H6 M3 E403a-d O13 H7 M3 E404a-d O13 H8 M3 E405a-d O13 H9 M3 E406a-d O14 H1 M3 E407a-d O14 H2 M3 E408a-d O14 H3 M3 E409a-d O14 H4 M3 E410a-d O14 H5 M3 E411a-d O14 H6 M3 E412a-d O14 H7 M3 E413a-d O14 H8 M3 E414a-d O14 H9 M3 E415a-d O15 H1 M3 E416a-d O15 H2 M3 E417a-d O15 H3 M3 E418a-d O15 H4 M3 E419a-d O15 H5 M3 E420a-d O15 H6 M3 E421a-d O15 H7 M3 E422a-d O15 H8 M3 E423a-d O15 H9 M3 E424a-d O16 H1 M3 E425a-d O16 H2 M3 E426a-d O16 H3 M3 E427a-d O16 H4 M3 E428a-d O16 H5 M3 E429a-d O16 H6 M3 E430a-d O16 H7 M3 E431a-d O16 H8 M3 E432a-d O16 H9 M3 E433a-d O1 H1 M4 E434a-d O1 H2 M4 E435a-d O1 H3 M4 E436a-d O1 H4 M4 E437a-d O1 H5 M4 E438a-d O1 H6 M4 E439a-d O1 H7 M4 E440a-d O1 H8 M4 E441a-d O1 H9 M4 E442a-d O2 H1 M4 E443a-d O2 H2 M4 E444a-d O2 H3 M4 E445a-d O2 H4 M4 E446a-d O2 H5 M4 E447a-d O2 H6 M4 E448a-d O2 H7 M4 E449a-d O2 H8 M4 E450a-d O2 H9 M4 E451a-d O3 H1 M4 E452a-d O3 H2 M4 E453a-d O3 H3 M4 E454a-d O3 H4 M4 E455a-d O3 H5 M4 E456a-d O3 H6 M4 E457a-d O3 H7 M4 E458a-d O3 H8 M4 E459a-d O3 H9 M4 E460a-d O4 H1 M4 E461a-d O4 H2 M4 E462a-d O4 H3 M4 E463a-d O4 H4 M4 E464a-d O4 H5 M4 E465a-d O4 H6 M4 E466a-d O4 H7 M4 E467a-d O4 H8 M4 E468a-d O4 H9 M4 E469a-d O5 H1 M4 E470a-d O5 H2 M4 E471a-d O5 H3 M4 E472a-d O5 H4 M4 E473a-d O5 H5 M4 E474a-d O5 H6 M4 E475a-d O5 H7 M4 E476a-d O5 H8 M4 E477a-d O5 H9 M4 E478a-d O6 H1 M4 E479a-d O6 H2 M4 E480a-d O6 H3 M4 E481a-d O6 H4 M4 E482a-d O6 H5 M4 E483a-d O6 H6 M4 E484a-d O6 H7 M4 E485a-d O6 H8 M4 E486a-d O6 H9 M4 E487a-d O7 H1 M4 E488a-d O7 H2 M4 E489a-d O7 H3 M4 E490a-d O7 H4 M4 E491a-d O7 H5 M4 E492a-d O7 H6 M4 E493a-d O7 H7 M4 E494a-d O7 H8 M4 E495a-d O7 H9 M4 E496a-d O8 H1 M4 E497a-d O8 H2 M4 E498a-d O8 H3 M4 E499a-d O8 H4 M4 E500a-d O8 H5 M4 E501a-d O8 H6 M4 E502a-d O8 H7 M4 E503a-d O8 H8 M4 E504a-d O8 H9 M4 E505a-d O9 H1 M4 E506a-d O9 H2 M4 E507a-d O9 H3 M4 E508a-d O9 H4 M4 E509a-d O9 H5 M4 E510a-d O9 H6 M4 E511a-d O9 H7 M4 E512a-d O9 H8 M4 E513a-d O9 H9 M4 E514a-d O10 H1 M4 E515a-d O10 H2 M4 E516a-d O10 H3 M4 E517a-d O10 H4 M4 E518a-d O10 H5 M4 E519a-d O10 H6 M4 E520a-d O10 H7 M4 E521a-d O10 H8 M4 E522a-d O10 H9 M4 E523a-d O11 H1 M4 E524a-d O11 H2 M4 E525a-d O11 H3 M4 E526a-d O11 H4 M4 E527a-d O11 H5 M4 E528a-d O11 H6 M4 E529a-d O11 H7 M4 E530a-d O11 H8 M4 E531a-d O11 H9 M4 E532a-d O12 H1 M4 E533a-d O12 H2 M4 E534a-d O12 H3 M4 E535a-d O12 H4 M4 E536a-d O12 H5 M4 E537a-d O12 H6 M4 E538a-d O12 H7 M4 E539a-d O12 H8 M4 E540a-d O12 H9 M4 E541a-d O13 H1 M4 E542a-d O13 H2 M4 E543a-d O13 H3 M4 E544a-d O13 H4 M4 E545a-d O13 H5 M4 E546a-d O13 H6 M4 E547a-d O13 H7 M4 E548a-d O13 H8 M4 E549a-d O13 H9 M4 E550a-d O14 H1 M4 E551a-d O14 H2 M4 E552a-d O14 H3 M4 E553a-d O14 H4 M4 E554a-d O14 H5 M4 E555a-d O14 H6 M4 E556a-d O14 H7 M4 E557a-d O14 H8 M4 E558a-d O14 H9 M4 E559a-d O15 H1 M4 E560a-d O15 H2 M4 E561a-d O15 H3 M4 E562a-d O15 H4 M4 E563a-d O15 H5 M4 E564a-d O15 H6 M4 E565a-d O15 H7 M4 E566a-d O15 H8 M4 E567a-d O15 H9 M4 E568a-d O16 H1 M4 E569a-d O16 H2 M4 E570a-d O16 H3 M4 E571a-d O16 H4 M4 E572a-d O16 H5 M4 E573a-d O16 H6 M4 E574a-d O16 H7 M4 E575a-d O16 H8 M4 E576a-d O16 H9 M4 E577a-d O1 H1 M5 E578a-d O1 H2 M5 E579a-d O1 H3 M5 E580a-d O1 H4 M5 E581a-d O1 H5 M5 E582a-d O1 H6 M5 E583a-d O1 H7 M5 E584a-d O1 H8 M5 E585a-d O1 H9 M5 E586a-d O2 H1 M5 E587a-d O2 H2 M5 E588a-d O2 H3 M5 E589a-d O2 H4 M5 E590a-d O2 H5 M5 E591a-d O2 H6 M5 E592a-d O2 H7 M5 E593a-d O2 H8 M5 E594a-d O2 H9 M5 E595a-d O3 H1 M5 E596a-d O3 H2 M5 E597a-d O3 H3 M5 E598a-d O3 H4 M5 E599a-d O3 H5 M5 E600a-d O3 H6 M5 E601a-d O3 H7 M5 E602a-d O3 H8 M5 E603a-d O3 H9 M5 E604a-d O4 H1 M5 E605a-d O4 H2 M5 E606a-d O4 H3 M5 E607a-d O4 H4 M5 E608a-d O4 H5 M5 E609a-d O4 H6 M5 E610a-d O4 H7 M5 E611a-d O4 H8 M5 E612a-d O4 H9 M5 E613a-d O5 H1 M5 E614a-d O5 H2 M5 E615a-d O5 H3 M5 E616a-d O5 H4 M5 E617a-d O5 H5 M5 E618a-d O5 H6 M5 E619a-d O5 H7 M5 E620a-d O5 H8 M5 E621a-d O5 H9 M5 E622a-d O6 H1 M5 E623a-d O6 H2 M5 E624a-d O6 H3 M5 E625a-d O6 H4 M5 E626a-d O6 H5 M5 E627a-d O6 H6 M5 E628a-d O6 H7 M5 E629a-d O6 H8 M5 E630a-d O6 H9 M5 E631a-d O7 H1 M5 E632a-d O7 H2 M5 E633a-d O7 H3 M5 E634a-d O7 H4 M5 E635a-d O7 H5 M5 E636a-d O7 H6 M5 E637a-d O7 H7 M5 E638a-d O7 H8 M5 E639a-d O7 H9 M5 E640a-d O8 H1 M5 E641a-d O8 H2 M5 E642a-d O8 H3 M5 E643a-d O8 H4 M5 E644a-d O8 H5 M5 E645a-d O8 H6 M5 E646a-d O8 H7 M5 E647a-d O8 H8 M5 E648a-d O8 H9 M5 E649a-d O9 H1 M5 E650a-d O9 H2 M5 E651a-d O9 H3 M5 E652a-d O9 H4 M5 E653a-d O9 H5 M5 E654a-d O9 H6 M5 E655a-d O9 H7 M5 E656a-d O9 H8 M5 E657a-d O9 H9 M5 E658a-d O10 H1 M5 E659a-d O10 H2 M5 E660a-d O10 H3 M5 E661a-d O10 H4 M5 E662a-d O10 H5 M5 E663a-d O10 H6 M5 E664a-d O10 H7 M5 E665a-d O10 H8 M5 E666a-d O10 H9 M5 E667a-d O11 H1 M5 E668a-d O11 H2 M5 E669a-d O11 H3 M5 E670a-d O11 H4 M5 E671a-d O11 H5 M5 E672a-d O11 H6 M5 E673a-d O11 H7 M5 E674a-d O11 H8 M5 E675a-d O11 H9 M5 E676a-d O12 H1 M5 E677a-d O12 H2 M5 E678a-d O12 H3 M5 E679a-d O12 H4 M5 E680a-d O12 H5 M5 E681a-d O12 H6 M5 E682a-d O12 H7 M5 E683a-d O12 H8 M5 E684a-d O12 H9 M5 E685a-d O13 H1 M5 E686a-d O13 H2 M5 E687a-d O13 H3 M5 E688a-d O13 H4 M5 E689a-d O13 H5 M5 E690a-d O13 H6 M5 E691a-d O13 H7 M5 E692a-d O13 H8 M5 E693a-d O13 H9 M5 E694a-d O14 H1 M5 E695a-d O14 H2 M5 E696a-d O14 H3 M5 E697a-d O14 H4 M5 E698a-d O14 H5 M5 E699a-d O14 H6 M5 E700a-d O14 H7 M5 E701a-d O14 H8 M5 E702a-d O14 H9 M5 E703a-d O15 H1 M5 E704a-d O15 H2 M5 E705a-d O15 H3 M5 E706a-d O15 H4 M5 E707a-d O15 H5 M5 E708a-d O15 H6 M5 E709a-d O15 H7 M5 E710a-d O15 H8 M5 E711a-d O15 H9 M5 E712a-d O16 H1 M5 E713a-d O16 H2 M5 E714a-d O16 H3 M5 E715a-d O16 H4 M5 E716a-d O16 H5 M5 E717a-d O16 H6 M5 E718a-d O16 H7 M5 E719a-d O16 H8 M5 E720a-d O16 H9 M5 E721a-d O1 H1 M6 E722a-d O1 H2 M6 E723a-d O1 H3 M6 E724a-d O1 H4 M6 E725a-d O1 H5 M6 E726a-d O1 H6 M6 E727a-d O1 H7 M6 E728a-d O1 H8 M6 E729a-d O1 H9 M6 E730a-d O2 H1 M6 E731a-d O2 H2 M6 E732a-d O2 H3 M6 E733a-d O2 H4 M6 E734a-d O2 H5 M6 E735a-d O2 H6 M6 E736a-d O2 H7 M6 E737a-d O2 H8 M6 E738a-d O2 H9 M6 E739a-d O3 H1 M6 E740a-d O3 H2 M6 E741a-d O3 H3 M6 E742a-d O3 H4 M6 E743a-d O3 H5 M6 E744a-d O3 H6 M6 E745a-d O3 H7 M6 E746a-d O3 H8 M6 E747a-d O3 H9 M6 E748a-d O4 H1 M6 E749a-d O4 H2 M6 E750a-d O4 H3 M6 E751a-d O4 H4 M6 E752a-d O4 H5 M6 E753a-d O4 H6 M6 E754a-d O4 H7 M6 E755a-d O4 H8 M6 E756a-d O4 H9 M6 E757a-d O5 H1 M6 E758a-d O5 H2 M6 E759a-d O5 H3 M6 E760a-d O5 H4 M6 E761a-d O5 H5 M6 E762a-d O5 H6 M6 E763a-d O5 H7 M6 E764a-d O5 H8 M6 E765a-d O5 H9 M6 E766a-d O6 H1 M6 E767a-d O6 H2 M6 E768a-d O6 H3 M6 E769a-d O6 H4 M6 E770a-d O6 H5 M6 E771a-d O6 H6 M6 E772a-d O6 H7 M6 E773a-d O6 H8 M6 E774a-d O6 H9 M6 E775a-d O7 H1 M6 E776a-d O7 H2 M6 E777a-d O7 H3 M6 E778a-d O7 H4 M6 E779a-d O7 H5 M6 E780a-d O7 H6 M6 E781a-d O7 H7 M6 E782a-d O7 H8 M6 E783a-d O7 H9 M6 E784a-d O8 H1 M6 E785a-d O8 H2 M6 E786a-d O8 H3 M6 E787a-d O8 H4 M6 E788a-d O8 H5 M6 E789a-d O8 H6 M6 E790a-d O8 H7 M6 E791a-d O8 H8 M6 E792a-d O8 H9 M6 E793a-d O9 H1 M6 E794a-d O9 H2 M6 E795a-d O9 H3 M6 E796a-d O9 H4 M6 E797a-d O9 H5 M6 E798a-d O9 H6 M6 E799a-d O9 H7 M6 E800a-d O9 H8 M6 E801a-d O9 H9 M6 E802a-d O10 H1 M6 E803a-d O10 H2 M6 E804a-d O10 H3 M6 E805a-d O10 H4 M6 E806a-d O10 H5 M6 E807a-d O10 H6 M6 E808a-d O10 H7 M6 E809a-d O10 H8 M6 E810a-d O10 H9 M6 E811a-d O11 H1 M6 E812a-d O11 H2 M6 E813a-d O11 H3 M6 E814a-d O11 H4 M6 E815a-d O11 H5 M6 E816a-d O11 H6 M6 E817a-d O11 H7 M6 E818a-d O11 H8 M6 E819a-d O11 H9 M6 E820a-d O12 H1 M6 E821a-d O12 H2 M6 E822a-d O12 H3 M6 E823a-d O12 H4 M6 E824a-d O12 H5 M6 E825a-d O12 H6 M6 E826a-d O12 H7 M6 E827a-d O12 H8 M6 E828a-d O12 H9 M6 E829a-d O13 H1 M6 E830a-d O13 H2 M6 E831a-d O13 H3 M6 E832a-d O13 H4 M6 E833a-d O13 H5 M6 E834a-d O13 H6 M6 E835a-d O13 H7 M6 E836a-d O13 H8 M6 E837a-d O13 H9 M6 E838a-d O14 H1 M6 E839a-d O14 H2 M6 E840a-d O14 H3 M6 E841a-d O14 H4 M6 E842a-d O14 H5 M6 E843a-d O14 H6 M6 E844a-d O14 H7 M6 E845a-d O14 H8 M6 E846a-d O14 H9 M6 E847a-d O15 H1 M6 E848a-d O15 H2 M6 E849a-d O15 H3 M6 E850a-d O15 H4 M6 E851a-d O15 H5 M6 E852a-d O15 H6 M6 E853a-d O15 H7 M6 E854a-d O15 H8 M6 E855a-d O15 H9 M6 E856a-d O16 H1 M6 E857a-d O16 H2 M6 E858a-d O16 H3 M6 E859a-d O16 H4 M6 E860a-d O16 H5 M6 E861a-d O16 H6 M6 E862a-d O16 H7 M6 E863a-d O16 H8 M6 E864a-d O16 H9 M6 E865a-d O1 H1 M7 E866a-d O1 H2 M7 E867a-d O1 H3 M7 E868a-d O1 H4 M7 E869a-d O1 H5 M7 E870a-d O1 H6 M7 E871a-d O1 H7 M7 E872a-d O1 H8 M7 E873a-d O1 H9 M7 E874a-d O2 H1 M7 E875a-d O2 H2 M7 E876a-d O2 H3 M7 E877a-d O2 H4 M7 E878a-d O2 H5 M7 E879a-d O2 H6 M7 E880a-d O2 H7 M7 E881a-d O2 H8 M7 E882a-d O2 H9 M7 E883a-d O3 H1 M7 E884a-d O3 H2 M7 E885a-d O3 H3 M7 E886a-d O3 H4 M7 E887a-d O3 H5 M7 E888a-d O3 H6 M7 E889a-d O3 H7 M7 E890a-d O3 H8 M7 E891a-d O3 H9 M7 E892a-d O4 H1 M7 E893a-d O4 H2 M7 E894a-d O4 H3 M7 E895a-d O4 H4 M7 E896a-d O4 H5 M7 E897a-d O4 H6 M7 E898a-d O4 H7 M7 E899a-d O4 H8 M7 E900a-d O4 H9 M7 E901a-d O5 H1 M7 E902a-d O5 H2 M7 E903a-d O5 H3 M7 E904a-d O5 H4 M7 E905a-d O5 H5 M7 E906a-d O5 H6 M7 E907a-d O5 H7 M7 E908a-d O5 H8 M7 E909a-d O5 H9 M7 E910a-d O6 H1 M7 E911a-d O6 H2 M7 E912a-d O6 H3 M7 E913a-d O6 H4 M7 E914a-d O6 H5 M7 E915a-d O6 H6 M7 E916a-d O6 H7 M7 E917a-d O6 H8 M7 E918a-d O6 H9 M7 E919a-d O7 H1 M7 E920a-d O7 H2 M7 E921a-d O7 H3 M7 E922a-d O7 H4 M7 E923a-d O7 H5 M7 E924a-d O7 H6 M7 E925a-d O7 H7 M7 E926a-d O7 H8 M7 E927a-d O7 H9 M7 E928a-d O8 H1 M7 E929a-d O8 H2 M7 E930a-d O8 H3 M7 E931a-d O8 H4 M7 E932a-d O8 H5 M7 E933a-d O8 H6 M7 E934a-d O8 H7 M7 E935a-d O8 H8 M7 E936a-d O8 H9 M7 E937a-d O9 H1 M7 E938a-d O9 H2 M7 E939a-d O9 H3 M7 E940a-d O9 H4 M7 E941a-d O9 H5 M7 E942a-d O9 H6 M7 E943a-d O9 H7 M7 E944a-d O9 H8 M7 E945a-d O9 H9 M7 E946a-d O10 H1 M7 E947a-d O10 H2 M7 E948a-d O10 H3 M7 E949a-d O10 H4 M7 E950a-d O10 H5 M7 E951a-d O10 H6 M7 E952a-d O10 H7 M7 E953a-d O10 H8 M7 E954a-d O10 H9 M7 E955a-d O11 H1 M7 E956a-d O11 H2 M7 E957a-d O11 H3 M7 E958a-d O11 H4 M7 E959a-d O11 H5 M7 E960a-d O11 H6 M7 E961a-d O11 H7 M7 E962a-d O11 H8 M7 E963a-d O11 H9 M7 E964a-d O12 H1 M7 E965a-d O12 H2 M7 E966a-d O12 H3 M7 E967a-d O12 H4 M7 E968a-d O12 H5 M7 E969a-d O12 H6 M7 E970a-d O12 H7 M7 E971a-d O12 H8 M7 E972a-d O12 H9 M7 E973a-d O13 H1 M7 E974a-d O13 H2 M7 E975a-d O13 H3 M7 E976a-d O13 H4 M7 E977a-d O13 H5 M7 E978a-d O13 H6 M7 E979a-d O13 H7 M7 E980a-d O13 H8 M7 E981a-d O13 H9 M7 E982a-d O14 H1 M7 E983a-d O14 H2 M7 E984a-d O14 H3 M7 E985a-d O14 H4 M7 E986a-d O14 H5 M7 E987a-d O14 H6 M7 E988a-d O14 H7 M7 E989a-d O14 H8 M7 E990a-d O14 H9 M7 E991a-d O15 H1 M7 E992a-d O15 H2 M7 E993a-d O15 H3 M7 E994a-d O15 H4 M7 E995a-d O15 H5 M7 E996a-d O15 H6 M7 E997a-d O15 H7 M7 E998a-d O15 H8 M7 E999a-d O15 H9 M7 E1000a-d O16 H1 M7 E1001a-d O16 H2 M7 E1002a-d O16 H3 M7 E1003a-d O16 H4 M7 E1004a-d O16 H5 M7 E1005a-d O16 H6 M7 E1006a-d O16 H7 M7 E1007a-d O16 H8 M7 E1008a-d O16 H9 M7 E1009a-d O1 H1 M8 E1010a-d O1 H2 M8 E1011a-d O1 H3 M8 E1012a-d O1 H4 M8 E1013a-d O1 H5 M8 E1014a-d O1 H6 M8 E1015a-d O1 H7 M8 E1016a-d O1 H8 M8 E1017a-d O1 H9 M8 E1018a-d O2 H1 M8 E1019a-d O2 H2 M8 E1020a-d O2 H3 M8 E1021a-d O2 H4 M8 E1022a-d O2 H5 M8 E1023a-d O2 H6 M8 E1024a-d O2 H7 M8 E1025a-d O2 H8 M8 E1026a-d O2 H9 M8 E1027a-d O3 H1 M8 E1028a-d O3 H2 M8 E1029a-d O3 H3 M8 E1030a-d O3 H4 M8 E1031a-d O3 H5 M8 E1032a-d O3 H6 M8 E1033a-d O3 H7 M8 E1034a-d O3 H8 M8 E1035a-d O3 H9 M8 E1036a-d O4 H1 M8 E1037a-d O4 H2 M8 E1038a-d O4 H3 M8 E1039a-d O4 H4 M8 E1040a-d O4 H5 M8 E1041a-d O4 H6 M8 E1042a-d O4 H7 M8 E1043a-d O4 H8 M8 E1044a-d O4 H9 M8 E1045a-d O5 H1 M8 E1046a-d O5 H2 M8 E1047a-d O5 H3 M8 E1048a-d O5 H4 M8 E1049a-d O5 H5 M8 E1050a-d O5 H6 M8 E1051a-d O5 H7 M8 E1052a-d O5 H8 M8 E1053a-d O5 H9 M8 E1054a-d O6 H1 M8 E1055a-d O6 H2 M8 E1056a-d O6 H3 M8 E1057a-d O6 H4 M8 E1058a-d O6 H5 M8 E1059a-d O6 H6 M8 E1060a-d O6 H7 M8 E1061a-d O6 H8 M8 E1062a-d O6 H9 M8 E1063a-d O7 H1 M8 E1064a-d O7 H2 M8 E1065a-d O7 H3 M8 E1066a-d O7 H4 M8 E1067a-d O7 H5 M8 E1068a-d O7 H6 M8 E1069a-d O7 H7 M8 E1070a-d O7 H8 M8 E1071a-d O7 H9 M8 E1072a-d O8 H1 M8 E1073a-d O8 H2 M8 E1074a-d O8 H3 M8 E1075a-d O8 H4 M8 E1076a-d O8 H5 M8 E1077a-d O8 H6 M8 E1078a-d O8 H7 M8 E1079a-d O8 H8 M8 E1080a-d O8 H9 M8 E1081a-d O9 H1 M8 E1082a-d O9 H2 M8 E1083a-d O9 H3 M8 E1084a-d O9 H4 M8 E1085a-d O9 H5 M8 E1086a-d O9 H6 M8 E1087a-d O9 H7 M8 E1088a-d O9 H8 M8 E1089a-d O9 H9 M8 E1090a-d O10 H1 M8 E1091a-d O10 H2 M8 E1092a-d O10 H3 M8 E1093a-d O10 H4 M8 E1094a-d O10 H5 M8 E1095a-d O10 H6 M8 E1096a-d O10 H7 M8 E1097a-d O10 H8 M8 E1098a-d O10 H9 M8 E1099a-d O11 H1 M8 E1100a-d O11 H2 M8 E1101a-d O11 H3 M8 E1102a-d O11 H4 M8 E1103a-d O11 H5 M8 E1104a-d O11 H6 M8 E1105a-d O11 H7 M8 E1106a-d O11 H8 M8 E1107a-d O11 H9 M8 E1108a-d O12 H1 M8 E1109a-d O12 H2 M8 E1110a-d O12 H3 M8 E1111a-d O12 H4 M8 E1112a-d O12 H5 M8 E1113a-d O12 H6 M8 E1114a-d O12 H7 M8 E1115a-d O12 H8 M8 E1116a-d O12 H9 M8 E1117a-d O13 H1 M8 E1118a-d O13 H2 M8 E1119a-d O13 H3 M8 E1120a-d O13 H4 M8 E1121a-d O13 H5 M8 E1122a-d O13 H6 M8 E1123a-d O13 H7 M8 E1124a-d O13 H8 M8 E1125a-d O13 H9 M8 E1126a-d O14 H1 M8 E1127a-d O14 H2 M8 E1128a-d O14 H3 M8 E1129a-d O14 H4 M8 E1130a-d O14 H5 M8 E1131a-d O14 H6 M8 E1132a-d O14 H7 M8 E1133a-d O14 H8 M8 E1134a-d O14 H9 M8 E1135a-d O15 H1 M8 E1136a-d O15 H2 M8 E1137a-d O15 H3 M8 E1138a-d O15 H4 M8 E1139a-d O15 H5 M8 E1140a-d O15 H6 M8 E1141a-d O15 H7 M8 E1142a-d O15 H8 M8 E1143a-d O15 H9 M8 E1144a-d O16 H1 M8 E1145a-d O16 H2 M8 E1146a-d O16 H3 M8 E1147a-d O16 H4 M8 E1148a-d O16 H5 M8 E1149a-d O16 H6 M8 E1150a-d O16 H7 M8 E1151a-d O16 H8 M8 E1152a-d O16 H9 M8 E1153a-d O1 H1 M9 E1154a-d O1 H2 M9 E1155a-d O1 H3 M9 E1156a-d O1 H4 M9 E1157a-d O1 H5 M9 E1158a-d O1 H6 M9 E1159a-d O1 H7 M9 E1160a-d O1 H8 M9 E1161a-d O1 H9 M9 E1162a-d O2 H1 M9 E1163a-d O2 H2 M9 E1164a-d O2 H3 M9 E1165a-d O2 H4 M9 E1166a-d O2 H5 M9 E1167a-d O2 H6 M9 E1168a-d O2 H7 M9 E1169a-d O2 H8 M9 E1170a-d O2 H9 M9 E1171a-d O3 H1 M9 E1172a-d O3 H2 M9 E1173a-d O3 H3 M9 E1174a-d O3 H4 M9 E1175a-d O3 H5 M9 E1176a-d O3 H6 M9 E1177a-d O3 H7 M9 E1178a-d O3 H8 M9 E1179a-d O3 H9 M9 E1180a-d O4 H1 M9 E1181a-d O4 H2 M9 E1182a-d O4 H3 M9 E1183a-d O4 H4 M9 E1184a-d O4 H5 M9 E1185a-d O4 H6 M9 E1186a-d O4 H7 M9 E1187a-d O4 H8 M9 E1188a-d O4 H9 M9 E1189a-d O5 H1 M9 E1190a-d O5 H2 M9 E1191a-d O5 H3 M9 E1192a-d O5 H4 M9 E1193a-d O5 H5 M9 E1194a-d O5 H6 M9 E1195a-d O5 H7 M9 E1196a-d O5 H8 M9 E1197a-d O5 H9 M9 E1198a-d O6 H1 M9 E1199a-d O6 H2 M9 E1200a-d O6 H3 M9 E1201a-d O6 H4 M9 E1202a-d O6 H5 M9 E1203a-d O6 H6 M9 E1204a-d O6 H7 M9 E1205a-d O6 H8 M9 E1206a-d O6 H9 M9 E1207a-d O7 H1 M9 E1208a-d O7 H2 M9 E1209a-d O7 H3 M9 E1210a-d O7 H4 M9 E1211a-d O7 H5 M9 E1212a-d O7 H6 M9 E1213a-d O7 H7 M9 E1214a-d O7 H8 M9 E1215a-d O7 H9 M9 E1216a-d O8 H1 M9 E1217a-d O8 H2 M9 E1218a-d O8 H3 M9 E1219a-d O8 H4 M9 E1220a-d O8 H5 M9 E1221a-d O8 H6 M9 E1222a-d O8 H7 M9 E1223a-d O8 H8 M9 E1224a-d O8 H9 M9 E1225a-d O9 H1 M9 E1226a-d O9 H2 M9 E1227a-d O9 H3 M9 E1228a-d O9 H4 M9 E1229a-d O9 H5 M9 E1230a-d O9 H6 M9 E1231a-d O9 H7 M9 E1232a-d O9 H8 M9 E1233a-d O9 H9 M9 E1234a-d O10 H1 M9 E1235a-d O10 H2 M9 E1236a-d O10 H3 M9 E1237a-d O10 H4 M9 E1238a-d O10 H5 M9 E1239a-d O10 H6 M9 E1240a-d O10 H7 M9 E1241a-d O10 H8 M9 E1242a-d O10 H9 M9 E1243a-d O11 H1 M9 E1244a-d O11 H2 M9 E1245a-d O11 H3 M9 E1246a-d O11 H4 M9 E1247a-d O11 H5 M9 E1248a-d O11 H6 M9 E1249a-d O11 H7 M9 E1250a-d O11 H8 M9 E1251a-d O11 H9 M9 E1252a-d O12 H1 M9 E1253a-d O12 H2 M9 E1254a-d O12 H3 M9 E1255a-d O12 H4 M9 E1256a-d O12 H5 M9 E1257a-d O12 H6 M9 E1258a-d O12 H7 M9 E1259a-d O12 H8 M9 E1260a-d O12 H9 M9 E1261a-d O13 H1 M9 E1262a-d O13 H2 M9 E1263a-d O13 H3 M9 E1264a-d O13 H4 M9 E1265a-d O13 H5 M9 E1266a-d O13 H6 M9 E1267a-d O13 H7 M9 E1268a-d O13 H8 M9 E1269a-d O13 H9 M9 E1270a-d O14 H1 M9 E1271a-d O14 H2 M9 E1272a-d O14 H3 M9 E1273a-d O14 H4 M9 E1274a-d O14 H5 M9 E1275a-d O14 H6 M9 E1276a-d O14 H7 M9 E1277a-d O14 H8 M9 E1278a-d O14 H9 M9 E1279a-d O15 H1 M9 E1280a-d O15 H2 M9 E1281a-d O15 H3 M9 E1282a-d O15 H4 M9 E1283a-d O15 H5 M9 E1284a-d O15 H6 M9 E1285a-d O15 H7 M9 E1286a-d O15 H8 M9 E1287a-d O15 H9 M9 E1288a-d O16 H1 M9 E1289a-d O16 H2 M9 E1290a-d O16 H3 M9 E1291a-d O16 H4 M9 E1292a-d O16 H5 M9 E1293a-d O16 H6 M9 E1294a-d O16 H7 M9 E1295a-d O16 H8 M9 E1296a-d O16 H9 M9 E1297a-d O1 H1 M10 E1298a-d O1 H2 M10 E1299a-d O1 H3 M10 E1300a-d O1 H4 M10 E1301a-d O1 H5 M10 E1302a-d O1 H6 M10 E1303a-d O1 H7 M10 E1304a-d O1 H8 M10 E1305a-d O1 H9 M10 E1306a-d O2 H1 M10 E1307a-d O2 H2 M10 E1308a-d O2 H3 M10 E1309a-d O2 H4 M10 E1310a-d O2 H5 M10 E1311a-d O2 H6 M10 E1312a-d O2 H7 M10 E1313a-d O2 H8 M10 E1314a-d O2 H9 M10 E1315a-d O3 H1 M10 E1316a-d O3 H2 M10 E1317a-d O3 H3 M10 E1318a-d O3 H4 M10 E1319a-d O3 H5 M10 E1320a-d O3 H6 M10 E1321a-d O3 H7 M10 E1322a-d O3 H8 M10 E1323a-d O3 H9 M10 E1324a-d O4 H1 M10 E1325a-d O4 H2 M10 E1326a-d O4 H3 M10 E1327a-d O4 H4 M10 E1328a-d O4 H5 M10 E1329a-d O4 H6 M10 E1330a-d O4 H7 M10 E1331a-d O4 H8 M10 E1332a-d O4 H9 M10 E1333a-d O5 H1 M10 E1334a-d O5 H2 M10 E1335a-d O5 H3 M10 E1336a-d O5 H4 M10 E1337a-d O5 H5 M10 E1338a-d O5 H6 M10 E1339a-d O5 H7 M10 E1340a-d O5 H8 M10 E1341a-d O5 H9 M10 E1342a-d O6 H1 M10 E1343a-d O6 H2 M10 E1344a-d O6 H3 M10 E1345a-d O6 H4 M10 E1346a-d O6 H5 M10 E1347a-d O6 H6 M10 E1348a-d O6 H7 M10 E1349a-d O6 H8 M10 E1350a-d O6 H9 M10 E1351a-d O7 H1 M10 E1352a-d O7 H2 M10 E1353a-d O7 H3 M10 E1354a-d O7 H4 M10 E1355a-d O7 H5 M10 E1356a-d O7 H6 M10 E1357a-d O7 H7 M10 E1358a-d O7 H8 M10 E1359a-d O7 H9 M10 E1360a-d O8 H1 M10 E1361a-d O8 H2 M10 E1362a-d O8 H3 M10 E1363a-d O8 H4 M10 E1364a-d O8 H5 M10 E1365a-d O8 H6 M10 E1366a-d O8 H7 M10 E1367a-d O8 H8 M10 E1368a-d O8 H9 M10 E1369a-d O9 H1 M10 E1370a-d O9 H2 M10 E1371a-d O9 H3 M10 E1372a-d O9 H4 M10 E1373a-d O9 H5 M10 E1374a-d O9 H6 M10 E1375a-d O9 H7 M10 E1376a-d O9 H8 M10 E1377a-d O9 H9 M10 E1378a-d O10 H1 M10 E1379a-d O10 H2 M10 E1380a-d O10 H3 M10 E1381a-d O10 H4 M10 E1382a-d O10 H5 M10 E1383a-d O10 H6 M10 E1384a-d O10 H7 M10 E1385a-d O10 H8 M10 E1386a-d O10 H9 M10 E1387a-d O11 H1 M10 E1388a-d O11 H2 M10 E1389a-d O11 H3 M10 E1390a-d O11 H4 M10 E1391a-d O11 H5 M10 E1392a-d O11 H6 M10 E1393a-d O11 H7 M10 E1394a-d O11 H8 M10 E1395a-d O11 H9 M10 E1396a-d O12 H1 M10 E1397a-d O12 H2 M10 E1398a-d O12 H3 M10 E1399a-d O12 H4 M10 E1400a-d O12 H5 M10 E1401a-d O12 H6 M10 E1402a-d O12 H7 M10 E1403a-d O12 H8 M10 E1404a-d O12 H9 M10 E1405a-d O13 H1 M10 E1406a-d O13 H2 M10 E1407a-d O13 H3 M10 E1408a-d O13 H4 M10 E1409a-d O13 H5 M10 E1410a-d O13 H6 M10 E1411a-d O13 H7 M10 E1412a-d O13 H8 M10 E1413a-d O13 H9 M10 E1414a-d O14 H1 M10 E1415a-d O14 H2 M10 E1416a-d O14 H3 M10 E1417a-d O14 H4 M10 E1418a-d O14 H5 M10 E1419a-d O14 H6 M10 E1420a-d O14 H7 M10 E1421a-d O14 H8 M10 E1422a-d O14 H9 M10 E1423a-d O15 H1 M10 E1424a-d O15 H2 M10 E1425a-d O15 H3 M10 E1426a-d O15 H4 M10 E1427a-d O15 H5 M10 E1428a-d O15 H6 M10 E1429a-d O15 H7 M10 E1430a-d O15 H8 M10 E1431a-d O15 H9 M10 E1432a-d O16 H1 M10 E1433a-d O16 H2 M10 E1434a-d O16 H3 M10 E1435a-d O16 H4 M10 E1436a-d O16 H5 M10 E1437a-d O16 H6 M10 E1438a-d O16 H7 M10 E1439a-d O16 H8 M10 E1440a-d O16 H9 M10 E1441a-d O1 H1 M11 E1442a-d O1 H2 M11 E1443a-d O1 H3 M11 E1444a-d O1 H4 M11 E1445a-d O1 H5 M11 E1446a-d O1 H6 M11 E1447a-d O1 H7 M11 E1448a-d O1 H8 M11 E1449a-d O1 H9 M11 E1450a-d O2 H1 M11 E1451a-d O2 H2 M11 E1452a-d O2 H3 M11 E1453a-d O2 H4 M11 E1454a-d O2 H5 M11 E1455a-d O2 H6 M11 E1456a-d O2 H7 M11 E1457a-d O2 H8 M11 E1458a-d O2 H9 M11 E1459a-d O3 H1 M11 E1460a-d O3 H2 M11 E1461a-d O3 H3 M11 E1462a-d O3 H4 M11 E1463a-d O3 H5 M11 E1464a-d O3 H6 M11 E1465a-d O3 H7 M11 E1466a-d O3 H8 M11 E1467a-d O3 H9 M11 E1468a-d O4 H1 M11 E1469a-d O4 H2 M11 E1470a-d O4 H3 M11 E1471a-d O4 H4 M11 E1472a-d O4 H5 M11 E1473a-d O4 H6 M11 E1474a-d O4 H7 M11 E1475a-d O4 H8 M11 E1476a-d O4 H9 M11 E1477a-d O5 H1 M11 E1478a-d O5 H2 M11 E1479a-d O5 H3 M11 E1480a-d O5 H4 M11 E1481a-d O5 H5 M11 E1482a-d O5 H6 M11 E1483a-d O5 H7 M11 E1484a-d O5 H8 M11 E1485a-d O5 H9 M11 E1486a-d O6 H1 M11 E1487a-d O6 H2 M11 E1488a-d O6 H3 M11 E1489a-d O6 H4 M11 E1490a-d O6 H5 M11 E1491a-d O6 H6 M11 E1492a-d O6 H7 M11 E1493a-d O6 H8 M11 E1494a-d O6 H9 M11 E1495a-d O7 H1 M11 E1496a-d O7 H2 M11 E1497a-d O7 H3 M11 E1498a-d O7 H4 M11 E1499a-d O7 H5 M11 E1500a-d O7 H6 M11 E1501a-d O7 H7 M11 E1502a-d O7 H8 M11 E1503a-d O7 H9 M11 E1504a-d O8 H1 M11 E1505a-d O8 H2 M11 E1506a-d O8 H3 M11 E1507a-d O8 H4 M11 E1508a-d O8 H5 M11 E1509a-d O8 H6 M11 E1510a-d O8 H7 M11 E1511a-d O8 H8 M11 E1512a-d O8 H9 M11 E1513a-d O9 H1 M11 E1514a-d O9 H2 M11 E1515a-d O9 H3 M11 E1516a-d O9 H4 M11 E1517a-d O9 H5 M11 E1518a-d O9 H6 M11 E1519a-d O9 H7 M11 E1520a-d O9 H8 M11 E1521a-d O9 H9 M11 E1522a-d O10 H1 M11 E1523a-d O10 H2 M11 E1524a-d O10 H3 M11 E1525a-d O10 H4 M11 E1526a-d O10 H5 M11 E1527a-d O10 H6 M11 E1528a-d O10 H7 M11 E1529a-d O10 H8 M11 E1530a-d O10 H9 M11 E1531a-d O11 H1 M11 E1532a-d O11 H2 M11 E1533a-d O11 H3 M11 E1534a-d O11 H4 M11 E1535a-d O11 H5 M11 E1536a-d O11 H6 M11 E1537a-d O11 H7 M11 E1538a-d O11 H8 M11 E1539a-d O11 H9 M11 E1540a-d O12 H1 M11 E1541a-d O12 H2 M11 E1542a-d O12 H3 M11 E1543a-d O12 H4 M11 E1544a-d O12 H5 M11 E1545a-d O12 H6 M11 E1546a-d O12 H7 M11 E1547a-d O12 H8 M11 E1548a-d O12 H9 M11 E1549a-d O13 H1 M11 E1550a-d O13 H2 M11 E1551a-d O13 H3 M11 E1552a-d O13 H4 M11 E1553a-d O13 H5 M11 E1554a-d O13 H6 M11 E1555a-d O13 H7 M11 E1556a-d O13 H8 M11 E1557a-d O13 H9 M11 E1558a-d O14 H1 M11 E1559a-d O14 H2 M11 E1560a-d O14 H3 M11 E1561a-d O14 H4 M11 E1562a-d O14 H5 M11 E1563a-d O14 H6 M11 E1564a-d O14 H7 M11 E1565a-d O14 H8 M11 E1566a-d O14 H9 M11 E1567a-d O15 H1 M11 E1568a-d O15 H2 M11 E1569a-d O15 H3 M11 E1570a-d O15 H4 M11 E1571a-d O15 H5 M11 E1572a-d O15 H6 M11 E1573a-d O15 H7 M11 E1574a-d O15 H8 M11 E1575a-d O15 H9 M11 E1576a-d O16 H1 M11 E1577a-d O16 H2 M11 E1578a-d O16 H3 M11 E1579a-d O16 H4 M11 E1580a-d O16 H5 M11 E1581a-d O16 H6 M11 E1582a-d O16 H7 M11 E1583a-d O16 H8 M11 E1584a-d O16 H9 M11 E1585a-d O1 H1 M12 E1586a-d O1 H2 M12 E1587a-d O1 H3 M12 E1588a-d O1 H4 M12 E1589a-d O1 H5 M12 E1590a-d O1 H6 M12 E1591a-d O1 H7 M12 E1592a-d O1 H8 M12 E1593a-d O1 H9 M12 E1594a-d O2 H1 M12 E1595a-d O2 H2 M12 E1596a-d O2 H3 M12 E1597a-d O2 H4 M12 E1598a-d O2 H5 M12 E1599a-d O2 H6 M12 E1600a-d O2 H7 M12 E1601a-d O2 H8 M12 E1602a-d O2 H9 M12 E1603a-d O3 H1 M12 E1604a-d O3 H2 M12 E1605a-d O3 H3 M12 E1606a-d O3 H4 M12 E1607a-d O3 H5 M12 E1608a-d O3 H6 M12 E1609a-d O3 H7 M12 E1610a-d O3 H8 M12 E1611a-d O3 H9 M12 E1612a-d O4 H1 M12 E1613a-d O4 H2 M12 E1614a-d O4 H3 M12 E1615a-d O4 H4 M12 E1616a-d O4 H5 M12 E1617a-d O4 H6 M12 E1618a-d O4 H7 M12 E1619a-d O4 H8 M12 E1620a-d O4 H9 M12 E1621a-d O5 H1 M12 E1622a-d O5 H2 M12 E1623a-d O5 H3 M12 E1624a-d O5 H4 M12 E1625a-d O5 H5 M12 E1626a-d O5 H6 M12 E1627a-d O5 H7 M12 E1628a-d O5 H8 M12 E1629a-d O5 H9 M12 E1630a-d O6 H1 M12 E1631a-d O6 H2 M12 E1632a-d O6 H3 M12 E1633a-d O6 H4 M12 E1634a-d O6 H5 M12 E1635a-d O6 H6 M12 E1636a-d O6 H7 M12 E1637a-d O6 H8 M12 E1638a-d O6 H9 M12 E1639a-d O7 H1 M12 E1640a-d O7 H2 M12 E1641a-d O7 H3 M12 E1642a-d O7 H4 M12 E1643a-d O7 H5 M12 E1644a-d O7 H6 M12 E1645a-d O7 H7 M12 E1646a-d O7 H8 M12 E1647a-d O7 H9 M12 E1648a-d O8 H1 M12 E1649a-d O8 H2 M12 E1650a-d O8 H3 M12 E1651a-d O8 H4 M12 E1652a-d O8 H5 M12 E1653a-d O8 H6 M12 E1654a-d O8 H7 M12 E1655a-d O8 H8 M12 E1656a-d O8 H9 M12 E1657a-d O9 H1 M12 E1658a-d O9 H2 M12 E1659a-d O9 H3 M12 E1660a-d O9 H4 M12 E1661a-d O9 H5 M12 E1662a-d O9 H6 M12 E1663a-d O9 H7 M12 E1664a-d O9 H8 M12 E1665a-d O9 H9 M12 E1666a-d O10 H1 M12 E1667a-d O10 H2 M12 E1668a-d O10 H3 M12 E1669a-d O10 H4 M12 E1670a-d O10 H5 M12 E1671a-d O10 H6 M12 E1672a-d O10 H7 M12 E1673a-d O10 H8 M12 E1674a-d O10 H9 M12 E1675a-d O11 H1 M12 E1676a-d O11 H2 M12 E1677a-d O11 H3 M12 E1678a-d O11 H4 M12 E1679a-d O11 H5 M12 E1680a-d O11 H6 M12 E1681a-d O11 H7 M12 E1682a-d O11 H8 M12 E1683a-d O11 H9 M12 E1684a-d O12 H1 M12 E1685a-d O12 H2 M12 E1686a-d O12 H3 M12 E1687a-d O12 H4 M12 E1688a-d O12 H5 M12 E1689a-d O12 H6 M12 E1690a-d O12 H7 M12 E1691a-d O12 H8 M12 E1692a-d O12 H9 M12 E1693a-d O13 H1 M12 E1694a-d O13 H2 M12 E1695a-d O13 H3 M12 E1696a-d O13 H4 M12 E1697a-d O13 H5 M12 E1698a-d O13 H6 M12 E1699a-d O13 H7 M12 E1700a-d O13 H8 M12 E1701a-d O13 H9 M12 E1702a-d O14 H1 M12 E1703a-d O14 H2 M12 E1704a-d O14 H3 M12 E1705a-d O14 H4 M12 E1706a-d O14 H5 M12 E1707a-d O14 H6 M12 E1708a-d O14 H7 M12 E1709a-d O14 H8 M12 E1710a-d O14 H9 M12 E1711a-d O15 H1 M12 E1712a-d O15 H2 M12 E1713a-d O15 H3 M12 E1714a-d O15 H4 M12 E1715a-d O15 H5 M12 E1716a-d O15 H6 M12 E1717a-d O15 H7 M12 E1718a-d O15 H8 M12 E1719a-d O15 H9 M12 E1720a-d O16 H1 M12 E1721a-d O16 H2 M12 E1722a-d O16 H3 M12 E1723a-d O16 H4 M12 E1724a-d O16 H5 M12 E1725a-d O16 H6 M12 E1726a-d O16 H7 M12 E1727a-d O16 H8 M12 E1728a-d O16 H9 M12 E1729a-d O1 H1 M13 E1730a-d O1 H2 M13 E1731a-d O1 H3 M13 E1732a-d O1 H4 M13 E1733a-d O1 H5 M13 E1734a-d O1 H6 M13 E1735a-d O1 H7 M13 E1736a-d O1 H8 M13 E1737a-d O1 H9 M13 E1738a-d O2 H1 M13 E1739a-d O2 H2 M13 E1740a-d O2 H3 M13 E1741a-d O2 H4 M13 E1742a-d O2 H5 M13 E1743a-d O2 H6 M13 E1744a-d O2 H7 M13 E1745a-d O2 H8 M13 E1746a-d O2 H9 M13 E1747a-d O3 H1 M13 E1748a-d O3 H2 M13 E1749a-d O3 H3 M13 E1750a-d O3 H4 M13 E1751a-d O3 H5 M13 E1752a-d O3 H6 M13 E1753a-d O3 H7 M13 E1754a-d O3 H8 M13 E1755a-d O3 H9 M13 E1756a-d O4 H1 M13 E1757a-d O4 H2 M13 E1758a-d O4 H3 M13 E1759a-d O4 H4 M13 E1760a-d O4 H5 M13 E1761a-d O4 H6 M13 E1762a-d O4 H7 M13 E1763a-d O4 H8 M13 E1764a-d O4 H9 M13 E1765a-d O5 H1 M13 E1766a-d O5 H2 M13 E1767a-d O5 H3 M13 E1768a-d O5 H4 M13 E1769a-d O5 H5 M13 E1770a-d O5 H6 M13 E1771a-d O5 H7 M13 E1772a-d O5 H8 M13 E1773a-d O5 H9 M13 E1774a-d O6 H1 M13 E1775a-d O6 H2 M13 E1776a-d O6 H3 M13 E1777a-d O6 H4 M13 E1778a-d O6 H5 M13 E1779a-d O6 H6 M13 E1780a-d O6 H7 M13 E1781a-d O6 H8 M13 E1782a-d O6 H9 M13 E1783a-d O7 H1 M13 E1784a-d O7 H2 M13 E1785a-d O7 H3 M13 E1786a-d O7 H4 M13 E1787a-d O7 H5 M13 E1788a-d O7 H6 M13 E1789a-d O7 H7 M13 E1790a-d O7 H8 M13 E1791a-d O7 H9 M13 E1792a-d O8 H1 M13 E1793a-d O8 H2 M13 E1794a-d O8 H3 M13 E1795a-d O8 H4 M13 E1796a-d O8 H5 M13 E1797a-d O8 H6 M13 E1798a-d O8 H7 M13 E1799a-d O8 H8 M13 E1800a-d O8 H9 M13 E1801a-d O9 H1 M13 E1802a-d O9 H2 M13 E1803a-d O9 H3 M13 E1804a-d O9 H4 M13 E1805a-d O9 H5 M13 E1806a-d O9 H6 M13 E1807a-d O9 H7 M13 E1808a-d O9 H8 M13 E1809a-d O9 H9 M13 E1810a-d O10 H1 M13 E1811a-d O10 H2 M13 E1812a-d O10 H3 M13 E1813a-d O10 H4 M13 E1814a-d O10 H5 M13 E1815a-d O10 H6 M13 E1816a-d O10 H7 M13 E1817a-d O10 H8 M13 E1818a-d O10 H9 M13 E1819a-d O11 H1 M13 E1820a-d O11 H2 M13 E1821a-d O11 H3 M13 E1822a-d O11 H4 M13 E1823a-d O11 H5 M13 E1824a-d O11 H6 M13 E1825a-d O11 H7 M13 E1826a-d O11 H8 M13 E1827a-d O11 H9 M13 E1828a-d O12 H1 M13 E1829a-d O12 H2 M13 E1830a-d O12 H3 M13 E1831a-d O12 H4 M13 E1832a-d O12 H5 M13 E1833a-d O12 H6 M13 E1834a-d O12 H7 M13 E1835a-d O12 H8 M13 E1836a-d O12 H9 M13 E1837a-d O13 H1 M13 E1838a-d O13 H2 M13 E1839a-d O13 H3 M13 E1840a-d O13 H4 M13 E1841a-d O13 H5 M13 E1842a-d O13 H6 M13 E1843a-d O13 H7 M13 E1844a-d O13 H8 M13 E1845a-d O13 H9 M13 E1846a-d O14 H1 M13 E1847a-d O14 H2 M13 E1848a-d O14 H3 M13 E1849a-d O14 H4 M13 E1850a-d O14 H5 M13 E1851a-d O14 H6 M13 E1852a-d O14 H7 M13 M13 E1853a-d O14 H8 M13 E1854a-d O14 H9 M13 E1855a-d O15 H1 M13 E1856a-d O15 H2 M13 E1857a-d O15 H3 M13 E1858a-d O15 H4 M13 E1859a-d O15 H5 M13 E1860a-d O15 H6 M13 E1861a-d O15 H7 M13 E1862a-d O15 H8 M13 E1863a-d O15 H9 M13 E1864a-d O16 H1 M13 E1865a-d O16 H2 M13 E1866a-d O16 H3 M13 E1867a-d O16 H4 M13 E1868a-d O16 H5 M13 E1869a-d O16 H6 M13 E1870a-d O16 H7 M13 E1871a-d O16 H8 M13 E1872a-d O16 H9 M13 E1873a-d O1 H1 M14 E1874a-d O1 H2 M14 E1875a-d O1 H3 M14 E1876a-d O1 H4 M14 E1877a-d O1 H5 M14 E1878a-d O1 H6 M14 E1879a-d O1 H7 M14 E1880a-d O1 H8 M14 E1881a-d O1 H9 M14 E1882a-d O2 H1 M14 E1883a-d O2 H2 M14 E1884a-d O2 H3 M14 E1885a-d O2 H4 M14 E1886a-d O2 H5 M14 E1887a-d O2 H6 M14 E1888a-d O2 H7 M14 E1889a-d O2 H8 M14 E1890a-d O2 H9 M14 E1891a-d O3 H1 M14 E1892a-d O3 H2 M14 E1893a-d O3 H3 M14 E1894a-d O3 H4 M14 E1895a-d O3 H5 M14 E1896a-d O3 H6 M14 E1897a-d O3 H7 M14 E1898a-d O3 H8 M14 E1899a-d O3 H9 M14 E1900a-d O4 H1 M14 E1901a-d O4 H2 M14 E1902a-d O4 H3 M14 E1903a-d O4 H4 M14 E1904a-d O4 H5 M14 E1905a-d O4 H6 M14 E1906a-d O4 H7 M14 E1907a-d O4 H8 M14 E1908a-d O4 H9 M14 E1909a-d O5 H1 M14 E1910a-d O5 H2 M14 E1911a-d O5 H3 M14 E1912a-d O5 H4 M14 E1913a-d O5 H5 M14 E1914a-d O5 H6 M14 E1915a-d O5 H7 M14 E1916a-d O5 H8 M14 E1917a-d O5 H9 M14 E1918a-d O6 H1 M14 E1919a-d O6 H2 M14 E1920a-d O6 H3 M14 E1921a-d O6 H4 M14 E1922a-d O6 H5 M14 E1923a-d O6 H6 M14 E1924a-d O6 H7 M14 E1925a-d O6 H8 M14 E1926a-d O6 H9 M14 E1927a-d O7 H1 M14 E1928a-d O7 H2 M14 E1929a-d O7 H3 M14 E1930a-d O7 H4 M14 E1931a-d O7 H5 M14 E1932a-d O7 H6 M14 E1933a-d O7 H7 M14 E1934a-d O7 H8 M14 E1935a-d O7 H9 M14 E1936a-d O8 H1 M14 E1937a-d O8 H2 M14 E1938a-d O8 H3 M14 E1939a-d O8 H4 M14 E1940a-d O8 H5 M14 E1941a-d O8 H6 M14 E1942a-d O8 H7 M14 E1943a-d O8 H8 M14 E1944a-d O8 H9 M14 E1945a-d O9 H1 M14 E1946a-d O9 H2 M14 E1947a-d O9 H3 M14 E1948a-d O9 H4 M14 E1949a-d O9 H5 M14 E1950a-d O9 H6 M14 E1951a-d O9 H7 M14 E1952a-d O9 H8 M14 E1953a-d O9 H9 M14 E1954a-d O10 H1 M14 E1955a-d O10 H2 M14 E1956a-d O10 H3 M14 E1957a-d O10 H4 M14 E1958a-d O10 H5 M14 E1959a-d O10 H6 M14 E1960a-d O10 H7 M14 E1961a-d O10 H8 M14 E1962a-d O10 H9 M14 E1963a-d O11 H1 M14 E1964a-d O11 H2 M14 E1965a-d O11 H3 M14 E1966a-d O11 H4 M14 E1967a-d O11 H5 M14 E1968a-d O11 H6 M14 E1969a-d O11 H7 M14 E1970a-d O11 H8 M14 E1971a-d O11 H9 M14 E1972a-d O12 H1 M14 E1973a-d O12 H2 M14 E1974a-d O12 H3 M14 E1975a-d O12 H4 M14 E1976a-d O12 H5 M14 E1977a-d O12 H6 M14 E1978a-d O12 H7 M14 E1979a-d O12 H8 M14 E1980a-d O12 H9 M14 E1981a-d O13 H1 M14 E1982a-d O13 H2 M14 E1983a-d O13 H3 M14 E1984a-d O13 H4 M14 E1985a-d O13 H5 M14 E1986a-d O13 H6 M14 E1987a-d O13 H7 M14 E1988a-d O13 H8 M14 E1989a-d O13 H9 M14 E1990a-d O14 H1 M14 E1991a-d O14 H2 M14 E1992a-d O14 H3 M14 E1993a-d O14 H4 M14 E1994a-d O14 H5 M14 E1995a-d O14 H6 M14 E1996a-d O14 H7 M14 E1997a-d O14 H8 M14 E1998a-d O14 H9 M14 E1999a-d O15 H1 M14 E2000a-d O15 H2 M14 E2001a-d O15 H3 M14 E2002a-d O15 H4 M14 E2003a-d O15 H5 M14 E2004a-d O15 H6 M14 E2005a-d O15 H7 M14 E2006a-d O15 H8 M14 E2007a-d O15 H9 M14 E2008a-d O16 H1 M14 E2009a-d O16 H2 M14 E2010a-d O16 H3 M14 E2011a-d O16 H4 M14 E2012a-d O16 H5 M14 E2013a-d O16 H6 M14 E2014a-d O16 H7 M14 E2015a-d O16 H8 M14 E2016a-d O16 H9 M14 E2017a-d O1 H1 M15 E2018a-d O1 H2 M15 E2019a-d O1 H3 M15 E2020a-d O1 H4 M15 E2021a-d O1 H5 M15 E2022a-d O1 H6 M15 E2023a-d O1 H7 M15 E2024a-d O1 H8 M15 E2025a-d O1 H9 M15 E2026a-d O2 H1 M15 E2027a-d O2 H2 M15 E2028a-d O2 H3 M15 E2029a-d O2 H4 M15 E2030a-d O2 H5 M15 E2031a-d O2 H6 M15 E2032a-d O2 H7 M15 E2033a-d O2 H8 M15 E2034a-d O2 H9 M15 E2035a-d O3 H1 M15 E2036a-d O3 H2 M15 E2037a-d O3 H3 M15 E2038a-d O3 H4 M15 E2039a-d O3 H5 M15 E2040a-d O3 H6 M15 E2041a-d O3 H7 M15 E2042a-d O3 H8 M15 E2043a-d O3 H9 M15 E2044a-d O4 H1 M15 E2045a-d O4 H2 M15 E2046a-d O4 H3 M15 E2047a-d O4 H4 M15 E2048a-d O4 H5 M15 E2049a-d O4 H6 M15 E2050a-d O4 H7 M15 E2051a-d O4 H8 M15 E2052a-d O4 H9 M15 E2053a-d O5 H1 M15 E2054a-d O5 H2 M15 E2055a-d O5 H3 M15 E2056a-d O5 H4 M15 E2057a-d O5 H5 M15 E2058a-d O5 H6 M15 E2059a-d O5 H7 M15 E2060a-d O5 H8 M15 E2061a-d O5 H9 M15 E2062a-d O6 H1 M15 E2063a-d O6 H2 M15 E2064a-d O6 H3 M15 E2065a-d O6 H4 M15 E2066a-d O6 H5 M15 E2067a-d O6 H6 M15 E2068a-d O6 H7 M15 E2069a-d O6 H8 M15 E2070a-d O6 H9 M15 E2071a-d O7 H1 M15 E2072a-d O7 H2 M15 E2073a-d O7 H3 M15 E2074a-d O7 H4 M15 E2075a-d O7 H5 M15 E2076a-d O7 H6 M15 E2077a-d O7 H7 M15 E2078a-d O7 H8 M15 E2079a-d O7 H9 M15 E2080a-d O8 H1 M15 E2081a-d O8 H2 M15 E2082a-d O8 H3 M15 E2083a-d O8 H4 M15 E2084a-d O8 H5 M15 E2085a-d O8 H6 M15 E2086a-d O8 H7 M15 E2087a-d O8 H8 M15 E2088a-d O8 H9 M15 E2089a-d O9 H1 M15 E2090a-d O9 H2 M15 E2091a-d O9 H3 M15 E2092a-d O9 H4 M15 E2093a-d O9 H5 M15 E2094a-d O9 H6 M15 E2095a-d O9 H7 M15 E2096a-d O9 H8 M15 E2097a-d O9 H9 M15 E2098a-d O10 H1 M15 E2099a-d O10 H2 M15 E2100a-d O10 H3 M15 E2101a-d O10 H4 M15 E2102a-d O10 H5 M15 E2103a-d O10 H6 M15 E2104a-d O10 H7 M15 E2105a-d O10 H8 M15 E2106a-d O10 H9 M15 E2107a-d O11 H1 M15 E2108a-d O11 H2 M15 E2109a-d O11 H3 M15 E2110a-d O11 H4 M15 E2111a-d O11 H5 M15 E2112a-d O11 H6 M15 E2113a-d O11 H7 M15 E2114a-d O11 H8 M15 E2115a-d O11 H9 M15 E2116a-d O12 H1 M15 E2117a-d O12 H2 M15 E2118a-d O12 H3 M15 E2119a-d O12 H4 M15 E2120a-d O12 H5 M15 E2121a-d O12 H6 M15 E2122a-d O12 H7 M15 E2123a-d O12 H8 M15 E2124a-d O12 H9 M15 E2125a-d O13 H1 M15 E2126a-d O13 H2 M15 E2127a-d O13 H3 M15 E2128a-d O13 H4 M15 E2129a-d O13 H5 M15 E2130a-d O13 H6 M15 E2131a-d O13 H7 M15 E2132a-d O13 H8 M15 E2133a-d O13 H9 M15 E2134a-d O14 H1 M15 E2135a-d O14 H2 M15 E2136a-d O14 H3 M15 E2137a-d O14 H4 M15 E2138a-d O14 H5 M15 E2139a-d O14 H6 M15 E2140a-d O14 H7 M15 E2141a-d O14 H8 M15 E2142a-d O14 H9 M15 E2143a-d O15 H1 M15 E2144a-d O15 H2 M15 E2145a-d O15 H3 M15 E2146a-d O15 H4 M15 E2147a-d O15 H5 M15 E2148a-d O15 H6 M15 E2149a-d O15 H7 M15 E2150a-d O15 H8 M15 E2151a-d O15 H9 M15 E2152a-d O16 H1 M15 E2153a-d O16 H2 M15 E2154a-d O16 H3 M15 E2155a-d O16 H4 M15 E2156a-d O16 H5 M15 E2157a-d O16 H6 M15 E2158a-d O16 H7 M15 E2159a-d O16 H8 M15 E2160a-d O16 H9 M15 E2161a-d O1 H1 M16 E2162a-d O1 H2 M16 E2163a-d O1 H3 M16 E2164a-d O1 H4 M16 E2165a-d O1 H5 M16 E2166a-d O1 H6 M16 E2167a-d O1 H7 M16 E2168a-d O1 H8 M16 E2169a-d O1 H9 M16 E2170a-d O2 H1 M16 E2171a-d O2 H2 M16 E2172a-d O2 H3 M16 E2173a-d O2 H4 M16 E2174a-d O2 H5 M16 E2175a-d O2 H6 M16 E2176a-d O2 H7 M16 E2177a-d O2 H8 M16 E2178a-d O2 H9 M16 E2179a-d O3 H1 M16 E2180a-d O3 H2 M16 E2181a-d O3 H3 M16 E2182a-d O3 H4 M16 E2183a-d O3 H5 M16 E2184a-d O3 H6 M16 E2185a-d O3 H7 M16 E2186a-d O3 H8 M16 E2187a-d O3 H9 M16 E2188a-d O4 H1 M16 E2189a-d O4 H2 M16 E2190a-d O4 H3 M16 E2191a-d O4 H4 M16 E2192a-d O4 H5 M16 E2193a-d O4 H6 M16 E2194a-d O4 H7 M16 E2195a-d O4 H8 M16 E2196a-d O4 H9 M16 E2197a-d O5 H1 M16 E2198a-d O5 H2 M16 E2199a-d O5 H3 M16 E2200a-d O5 H4 M16 E2201a-d O5 H5 M16 E2202a-d O5 H6 M16 E2203a-d O5 H7 M16 E2204a-d O5 H8 M16 E2205a-d O5 H9 M16 E2206a-d O6 H1 M16 E2207a-d O6 H2 M16 E2208a-d O6 H3 M16 E2209a-d O6 H4 M16 E2210a-d O6 H5 M16 E2211a-d O6 H6 M16 E2212a-d O6 H7 M16 E2213a-d O6 H8 M16 E2214a-d O6 H9 M16 E2215a-d O7 H1 M16 E2216a-d O7 H2 M16 E2217a-d O7 H3 M16 E2218a-d O7 H4 M16 E2219a-d O7 H5 M16 E2220a-d O7 H6 M16 E2221a-d O7 H7 M16 E2222a-d O7 H8 M16 E2223a-d O7 H9 M16 E2224a-d O8 H1 M16 E2225a-d O8 H2 M16 E2226a-d O8 H3 M16 E2227a-d O8 H4 M16 E2228a-d O8 H5 M16 E2229a-d O8 H6 M16 E2230a-d O8 H7 M16 E2231a-d O8 H8 M16 E2232a-d O8 H9 M16 E2233a-d O9 H1 M16 E2234a-d O9 H2 M16 E2235a-d O9 H3 M16 E2236a-d O9 H4 M16 E2237a-d O9 H5 M16 E2238a-d O9 H6 M16 E2239a-d O9 H7 M16 E2240a-d O9 H8 M16 E2241a-d O9 H9 M16 E2242a-d O10 H1 M16 E2243a-d O10 H2 M16 E2244a-d O10 H3 M16 E2245a-d O10 H4 M16 E2246a-d O10 H5 M16 E2247a-d O10 H6 M16 E2248a-d O10 H7 M16 E2249a-d O10 H8 M16 E2250a-d O10 H9 M16 E2251a-d O11 H1 M16 E2252a-d O11 H2 M16 E2253a-d O11 H3 M16 E2254a-d O11 H4 M16 E2255a-d O11 H5 M16 E2256a-d O11 H6 M16 E2257a-d O11 H7 M16 E2258a-d O11 H8 M16 E2259a-d O11 H9 M16 E2260a-d O12 H1 M16 E2261a-d O12 H2 M16 E2262a-d O12 H3 M16 E2263a-d O12 H4 M16 E2264a-d O12 H5 M16 E2265a-d O12 H6 M16 E2266a-d O12 H7 M16 E2267a-d O12 H8 M16 E2268a-d O12 H9 M16 E2269a-d O13 H1 M16 E2270a-d O13 H2 M16 E2271a-d O13 H3 M16 E2272a-d O13 H4 M16 E2273a-d O13 H5 M16 E2274a-d O13 H6 M16 E2275a-d O13 H7 M16 E2276a-d O13 H8 M16 E2277a-d O13 H9 M16 E2278a-d O14 H1 M16 E2279a-d O14 H2 M16 E2280a-d O14 H3 M16 E2281a-d O14 H4 M16 E2282a-d O14 H5 M16 E2283a-d O14 H6 M16 E2284a-d O14 H7 M16 E2285a-d O14 H8 M16 E2286a-d O14 H9 M16 E2287a-d O15 H1 M16 E2288a-d O15 H2 M16 E2289a-d O15 H3 M16 E2290a-d O15 H4 M16 E2291a-d O15 H5 M16 E2292a-d O15 H6 M16 E2293a-d O15 H7 M16 E2294a-d O15 H8 M16 E2295a-d O15 H9 M16 E2296a-d O16 H1 M16 E2297a-d O16 H2 M16 E2298a-d O16 H3 M16 E2299a-d O16 H4 M16 E2300a-d O16 H5 M16 E2301a-d O16 H6 M16 E2302a-d O16 H7 M16 E2303a-d O16 H8 M16 E2304a-d O16 H9 M16 E2305a-d O1 H1 M17 E2306a-d O1 H2 M17 E2307a-d O1 H3 M17 E2308a-d O1 H4 M17 E2309a-d O1 H5 M17 E2310a-d O1 H6 M17 E2311a-d O1 H7 M17 E2312a-d O1 H8 M17 E2313a-d O1 H9 M17 E2314a-d O2 H1 M17 E2315a-d O2 H2 M17 E2316a-d O2 H3 M17 E2317a-d O2 H4 M17 E2318a-d O2 H5 M17 E2319a-d O2 H6 M17 E2320a-d O2 H7 M17 E2321a-d O2 H8 M17 E2322a-d O2 H9 M17 E2323a-d O3 H1 M17 E2324a-d O3 H2 M17 E2325a-d O3 H3 M17 E2326a-d O3 H4 M17 E2327a-d O3 H5 M17 E2328a-d O3 H6 M17 E2329a-d O3 H7 M17 E2330a-d O3 H8 M17 E2331a-d O3 H9 M17 E2332a-d O4 H1 M17 E2333a-d O4 H2 M17 E2334a-d O4 H3 M17 E2335a-d O4 H4 M17 E2336a-d O4 H5 M17 E2337a-d O4 H6 M17 E2338a-d O4 H7 M17 E2339a-d O4 H8 M17 E2340a-d O4 H9 M17 E2341a-d O5 H1 M17 E2342a-d O5 H2 M17 E2343a-d O5 H3 M17 E2344a-d O5 H4 M17 E2345a-d O5 H5 M17 E2346a-d O5 H6 M17 E2347a-d O5 H7 M17 E2348a-d O5 H8 M17 E2349a-d O5 H9 M17 E2350a-d O6 H1 M17 E2351a-d O6 H2 M17 E2352a-d O6 H3 M17 E2353a-d O6 H4 M17 E2354a-d O6 H5 M17 E2355a-d O6 H6 M17 E2356a-d O6 H7 M17 E2357a-d O6 H8 M17 E2358a-d O6 H9 M17 E2359a-d O7 H1 M17 E2360a-d O7 H2 M17 E2361a-d O7 H3 M17 E2362a-d O7 H4 M17 E2363a-d O7 H5 M17 E2364a-d O7 H6 M17 E2365a-d O7 H7 M17 E2366a-d O7 H8 M17 E2367a-d O7 H9 M17 E2368a-d O8 H1 M17 E2369a-d O8 H2 M17 E2370a-d O8 H3 M17 E2371a-d O8 H4 M17 E2372a-d O8 H5 M17 E2373a-d O8 H6 M17 E2374a-d O8 H7 M17 E2375a-d O8 H8 M17 E2376a-d O8 H9 M17 E2377a-d O9 H1 M17 E2378a-d O9 H2 M17 E2379a-d O9 H3 M17 E2380a-d O9 H4 M17 E2381a-d O9 H5 M17 E2382a-d O9 H6 M17 E2383a-d O9 H7 M17 E2384a-d O9 H8 M17 E2385a-d O9 H9 M17 E2386a-d O10 H1 M17 E2387a-d O10 H2 M17 E2388a-d O10 H3 M17 E2389a-d O10 H4 M17 E2390a-d O10 H5 M17 E2391a-d O10 H6 M17 E2392a-d O10 H7 M17 E2393a-d O10 H8 M17 E2394a-d O10 H9 M17 E2395a-d O11 H1 M17 E2396a-d O11 H2 M17 E2397a-d O11 H3 M17 E2398a-d O11 H4 M17 E2399a-d O11 H5 M17 E2400a-d O11 H6 M17 E2401a-d O11 H7 M17 E2402a-d O11 H8 M17 E2403a-d O11 H9 M17 E2404a-d O12 H1 M17 E2405a-d O12 H2 M17 E2406a-d O12 H3 M17 E2407a-d O12 H4 M17 E2408a-d O12 H5 M17 E2409a-d O12 H6 M17 E2410a-d O12 H7 M17 E2411a-d O12 H8 M17 E2412a-d O12 H9 M17 E2413a-d O13 H1 M17 E2414a-d O13 H2 M17 E2415a-d O13 H3 M17 E2416a-d O13 H4 M17 E2417a-d O13 H5 M17 E2418a-d O13 H6 M17 E2419a-d O13 H7 M17 E2420a-d O13 H8 M17 E2421a-d O13 H9 M17 E2422a-d O14 H1 M17 E2423a-d O14 H2 M17 E2424a-d O14 H3 M17 E2425a-d O14 H4 M17 E2426a-d O14 H5 M17 E2427a-d O14 H6 M17 E2428a-d O14 H7 M17 E2429a-d O14 H8 M17 E2430a-d O14 H9 M17 E2431a-d O15 H1 M17 E2432a-d O15 H2 M17 E2433a-d O15 H3 M17 E2434a-d O15 H4 M17 E2435a-d O15 H5 M17 E2436a-d O15 H6 M17 E2437a-d O15 H7 M17 E2438a-d O15 H8 M17 E2439a-d O15 H9 M17 E2440a-d O16 H1 M17 E2441a-d O16 H2 M17 E2442a-d O16 H3 M17 E2443a-d O16 H4 M17 E2444a-d O16 H5 M17 E2445a-d O16 H6 M17 E2446a-d O16 H7 M17 E2447a-d O16 H8 M17 E2448a-d O16 H9 M17 E2449a-d O1 H1 M18 E2450a-d O1 H2 M18 E2451a-d O1 H3 M18 E2452a-d O1 H4 M18 E2453a-d O1 H5 M18 E2454a-d O1 H6 M18 E2455a-d O1 H7 M18 E2456a-d O1 H8 M18 E2457a-d O1 H9 M18 E2458a-d O2 H1 M18 E2459a-d O2 H2 M18 E2460a-d O2 H3 M18 E2461a-d O2 H4 M18 E2462a-d O2 H5 M18 E2463a-d O2 H6 M18 E2464a-d O2 H7 M18 E2465a-d O2 H8 M18 E2466a-d O2 H9 M18 E2467a-d O3 H1 M18 E2468a-d O3 H2 M18 E2469a-d O3 H3 M18 E2470a-d O3 H4 M18 E2471a-d O3 H5 M18 E2472a-d O3 H6 M18 E2473a-d O3 H7 M18 E2474a-d O3 H8 M18 E2475a-d O3 H9 M18 E2476a-d O4 H1 M18 E2477a-d O4 H2 M18 E2478a-d O4 H3 M18 E2479a-d O4 H4 M18 E2480a-d O4 H5 M18 E2481a-d O4 H6 M18 E2482a-d O4 H7 M18 E2483a-d O4 H8 M18 E2484a-d O4 H9 M18 E2485a-d O5 H1 M18 E2486a-d O5 H2 M18 E2487a-d O5 H3 M18 E2488a-d O5 H4 M18 E2489a-d O5 H5 M18 E2490a-d O5 H6 M18 E2491a-d O5 H7 M18 E2492a-d O5 H8 M18 E2493a-d O5 H9 M18 E2494a-d O6 H1 M18 E2495a-d O6 H2 M18 E2496a-d O6 H3 M18 E2497a-d O6 H4 M18 E2498a-d O6 H5 M18 E2499a-d O6 H6 M18 E2500a-d O6 H7 M18 E2501a-d O6 H8 M18 E2502a-d O6 H9 M18 E2503a-d O7 H1 M18 E2504a-d O7 H2 M18 E2505a-d O7 H3 M18 E2506a-d O7 H4 M18 E2507a-d O7 H5 M18 E2508a-d O7 H6 M18 E2509a-d O7 H7 M18 E2510a-d O7 H8 M18 E2511a-d O7 H9 M18 E2512a-d O8 H1 M18 E2513a-d O8 H2 M18 E2514a-d O8 H3 M18 E2515a-d O8 H4 M18 E2516a-d O8 H5 M18 E2517a-d O8 H6 M18 E2518a-d O8 H7 M18 E2519a-d O8 H8 M18 E2520a-d O8 H9 M18 E2521a-d O9 H1 M18 E2522a-d O9 H2 M18 E2523a-d O9 H3 M18 E2524a-d O9 H4 M18 E2525a-d O9 H5 M18 E2526a-d O9 H6 M18 E2527a-d O9 H7 M18 E2528a-d O9 H8 M18 E2529a-d O9 H9 M18 E2530a-d O10 H1 M18 E2531a-d O10 H2 M18 E2532a-d O10 H3 M18 E2533a-d O10 H4 M18 E2534a-d O10 H5 M18 E2535a-d O10 H6 M18 E2536a-d O10 H7 M18 E2537a-d O10 H8 M18 E2538a-d O10 H9 M18 E2539a-d O11 H1 M18 E2540a-d O11 H2 M18 E2541a-d O11 H3 M18 E2542a-d O11 H4 M18 E2543a-d O11 H5 M18 E2544a-d O11 H6 M18 E2545a-d O11 H7 M18 E2546a-d O11 H8 M18 E2547a-d O11 H9 M18 E2548a-d O12 H1 M18 E2549a-d O12 H2 M18 E2550a-d O12 H3 M18 E2551a-d O12 H4 M18 E2552a-d O12 H5 M18 E2553a-d O12 H6 M18 E2554a-d O12 H7 M18 E2555a-d O12 H8 M18 E2556a-d O12 H9 M18 E2557a-d O13 H1 M18 E2558a-d O13 H2 M18 E2559a-d O13 H3 M18 E2560a-d O13 H4 M18 E2561a-d O13 H5 M18 E2562a-d O13 H6 M18 E2563a-d O13 H7 M18 E2564a-d O13 H8 M18 E2565a-d O13 H9 M18 E2566a-d O14 H1 M18 E2567a-d O14 H2 M18 E2568a-d O14 H3 M18 E2569a-d O14 H4 M18 E2570a-d O14 H5 M18 E2571a-d O14 H6 M18 E2572a-d O14 H7 M18 E2573a-d O14 H8 M18 E2574a-d O14 H9 M18 E2575a-d O15 H1 M18 E2576a-d O15 H2 M18 E2577a-d O15 H3 M18 E2578a-d O15 H4 M18 E2579a-d O15 H5 M18 E2580a-d O15 H6 M18 E2581a-d O15 H7 M18 E2582a-d O15 H8 M18 E2583a-d O15 H9 M18 E2584a-d O16 H1 M18 E2585a-d O16 H2 M18 E2586a-d O16 H3 M18 E2587a-d O16 H4 M18 E2588a-d O16 H5 M18 E2589a-d O16 H6 M18 E2590a-d O16 H7 M18 E2591a-d O16 H8 M18 E2592a-d O16 H9 M18 E2593a-d O1 H1 M19 E2594a-d O1 H2 M19 E2595a-d O1 H3 M19 E2596a-d O1 H4 M19 E2597a-d O1 H5 M19 E2598a-d O1 H6 M19 E2599a-d O1 H7 M19 E2600a-d O1 H8 M19 E2601a-d O1 H9 M19 E2602a-d O2 H1 M19 E2603a-d O2 H2 M19 E2604a-d O2 H3 M19 E2605a-d O2 H4 M19 E2606a-d O2 H5 M19 E2607a-d O2 H6 M19 E2608a-d O2 H7 M19 E2609a-d O2 H8 M19 E2610a-d O2 H9 M19 E2611a-d O3 H1 M19 E2612a-d O3 H2 M19 E2613a-d O3 H3 M19 E2614a-d O3 H4 M19 E2615a-d O3 H5 M19 E2616a-d O3 H6 M19 E2617a-d O3 H7 M19 E2618a-d O3 H8 M19 E2619a-d O3 H9 M19 E2620a-d O4 H1 M19 E2621a-d O4 H2 M19 E2622a-d O4 H3 M19 E2623a-d O4 H4 M19 E2624a-d O4 H5 M19 E2625a-d O4 H6 M19 E2626a-d O4 H7 M19 E2627a-d O4 H8 M19 E2628a-d O4 H9 M19 E2629a-d O5 H1 M19 E2630a-d O5 H2 M19 E2631a-d O5 H3 M19 E2632a-d O5 H4 M19 E2633a-d O5 H5 M19 E2634a-d O5 H6 M19 E2635a-d O5 H7 M19 E2636a-d O5 H8 M19 E2637a-d O5 H9 M19 E2638a-d O6 H1 M19 E2639a-d O6 H2 M19 E2640a-d O6 H3 M19 E2641a-d O6 H4 M19 E2642a-d O6 H5 M19 E2643a-d O6 H6 M19 E2644a-d O6 H7 M19 E2645a-d O6 H8 M19 E2646a-d O6 H9 M19 E2647a-d O7 H1 M19 E2648a-d O7 H2 M19 E2649a-d O7 H3 M19 E2650a-d O7 H4 M19 E2651a-d O7 H5 M19 E2652a-d O7 H6 M19 E2653a-d O7 H7 M19 E2654a-d O7 H8 M19 E2655a-d O7 H9 M19 E2656a-d O8 H1 M19 E2657a-d O8 H2 M19 E2658a-d O8 H3 M19 E2659a-d O8 H4 M19 E2660a-d O8 H5 M19 E2661a-d O8 H6 M19 E2662a-d O8 H7 M19 E2663a-d O8 H8 M19 E2664a-d O8 H9 M19 E2665a-d O9 H1 M19 E2666a-d O9 H2 M19 E2667a-d O9 H3 M19 E2668a-d O9 H4 M19 E2669a-d O9 H5 M19 E2670a-d O9 H6 M19 E2671a-d O9 H7 M19 E2672a-d O9 H8 M19 E2673a-d O9 H9 M19 E2674a-d O10 H1 M19 E2675a-d O10 H2 M19 E2676a-d O10 H3 M19 E2677a-d O10 H4 M19 E2678a-d O10 H5 M19 E2679a-d O10 H6 M19 E2680a-d O10 H7 M19 E2681a-d O10 H8 M19 E2682a-d O10 H9 M19 E2683a-d O11 H1 M19 E2684a-d O11 H2 M19 E2685a-d O11 H3 M19 E2686a-d O11 H4 M19 E2687a-d O11 H5 M19 E2688a-d O11 H6 M19 E2689a-d O11 H7 M19 E2690a-d O11 H8 M19 E2691a-d O11 H9 M19 E2692a-d O12 H1 M19 E2693a-d O12 H2 M19 E2694a-d O12 H3 M19 E2695a-d O12 H4 M19 E2696a-d O12 H5 M19 E2697a-d O12 H6 M19 E2698a-d O12 H7 M19 E2699a-d O12 H8 M19 E2700a-d O12 H9 M19 E2701a-d O13 H1 M19 E2702a-d O13 H2 M19 E2703a-d O13 H3 M19 E2704a-d O13 H4 M19 E2705a-d O13 H5 M19 E2706a-d O13 H6 M19 E2707a-d O13 H7 M19 E2708a-d O13 H8 M19 E2709a-d O13 H9 M19 E2710a-d O14 H1 M19 E2711a-d O14 H2 M19 E2712a-d O14 H3 M19 E2713a-d O14 H4 M19 E2714a-d O14 H5 M19 E2715a-d O14 H6 M19 E2716a-d O14 H7 M19 E2717a-d O14 H8 M19 E2718a-d O14 H9 M19 E2719a-d O15 H1 M19 E2720a-d O15 H2 M19 E2721a-d O15 H3 M19 E2722a-d O15 H4 M19 E2723a-d O15 H5 M19 E2724a-d O15 H6 M19 E2725a-d O15 H7 M19 E2726a-d O15 H8 M19 E2727a-d O15 H9 M19 E2728a-d O16 H1 M19 E2729a-d O16 H2 M19 E2730a-d O16 H3 M19 E2731a-d O16 H4 M19 E2732a-d O16 H5 M19 E2733a-d O16 H6 M19 E2734a-d O16 H7 M19 E2735a-d O16 H8 M19 E2736a-d O16 H9 M19 E2737a-d O1 H1 M20 E2738a-d O1 H2 M20 E2739a-d O1 H3 M20 E2740a-d O1 H4 M20 E2741a-d O1 H5 M20 E2742a-d O1 H6 M20 E2743a-d O1 H7 M20 E2744a-d O1 H8 M20 E2745a-d O1 H9 M20 E2746a-d O2 H1 M20 E2747a-d O2 H2 M20 E2748a-d O2 H3 M20 E2749a-d O2 H4 M20 E2750a-d O2 H5 M20 E2751a-d O2 H6 M20 E2752a-d O2 H7 M20 E2753a-d O2 H8 M20 E2754a-d O2 H9 M20 E2755a-d O3 H1 M20 E2756a-d O3 H2 M20 E2757a-d O3 H3 M20 E2758a-d O3 H4 M20 E2759a-d O3 H5 M20 E2760a-d O3 H6 M20 E2761a-d O3 H7 M20 E2762a-d O3 H8 M20 E2763a-d O3 H9 M20 E2764a-d O4 H1 M20 E2765a-d O4 H2 M20 E2766a-d O4 H3 M20 E2767a-d O4 H4 M20 E2768a-d O4 H5 M20 E2769a-d O4 H6 M20 E2770a-d O4 H7 M20 E2771a-d O4 H8 M20 E2772a-d O4 H9 M20 E2773a-d O5 H1 M20 E2774a-d O5 H2 M20 E2775a-d O5 H3 M20 E2776a-d O5 H4 M20 E2777a-d O5 H5 M20 E2778a-d O5 H6 M20 E2779a-d O5 H7 M20 E2780a-d O5 H8 M20 E2781a-d O5 H9 M20 E2782a-d O6 H1 M20 E2783a-d O6 H2 M20 E2784a-d O6 H3 M20 E2785a-d O6 H4 M20 E2786a-d O6 H5 M20 E2787a-d O6 H6 M20 E2788a-d O6 H7 M20 E2789a-d O6 H8 M20 E2790a-d O6 H9 M20 E2791a-d O7 H1 M20 E2792a-d O7 H2 M20 E2793a-d O7 H3 M20 E2794a-d O7 H4 M20 E2795a-d O7 H5 M20 E2796a-d O7 H6 M20 E2797a-d O7 H7 M20 E2798a-d O7 H8 M20 E2799a-d O7 H9 M20 E2800a-d O8 H1 M20 E2801a-d O8 H2 M20 E2802a-d O8 H3 M20 E2803a-d O8 H4 M20 E2804a-d O8 H5 M20 E2805a-d O8 H6 M20 E2806a-d O8 H7 M20 E2807a-d O8 H8 M20 E2808a-d O8 H9 M20 E2809a-d O9 H1 M20 E2810a-d O9 H2 M20 E2811a-d O9 H3 M20 E2812a-d O9 H4 M20 E2813a-d O9 H5 M20 E2814a-d O9 H6 M20 E2815a-d O9 H7 M20 E2816a-d O9 H8 M20 E2817a-d O9 H9 M20 E2818a-d O10 H1 M20 E2819a-d O10 H2 M20 E2820a-d O10 H3 M20 E2821a-d O10 H4 M20 E2822a-d O10 H5 M20 E2823a-d O10 H6 M20 E2824a-d O10 H7 M20 E2825a-d O10 H8 M20 E2826a-d O10 H9 M20 E2827a-d O11 H1 M20 E2828a-d O11 H2 M20 E2829a-d O11 H3 M20 E2830a-d O11 H4 M20 E2831a-d O11 H5 M20 E2832a-d O11 H6 M20 E2833a-d O11 H7 M20 E2834a-d O11 H8 M20 E2835a-d O11 H9 M20 E2836a-d O12 H1 M20 E2837a-d O12 H2 M20 E2838a-d O12 H3 M20 E2839a-d O12 H4 M20 E2840a-d O12 H5 M20 E2841a-d O12 H6 M20 E2842a-d O12 H7 M20 E2843a-d O12 H8 M20 E2844a-d O12 H9 M20 E2845a-d O13 H1 M20 E2846a-d O13 H2 M20 E2847a-d O13 H3 M20 E2848a-d O13 H4 M20 E2849a-d O13 H5 M20 E2850a-d O13 H6 M20 E2851a-d O13 H7 M20 E2852a-d O13 H8 M20 E2853a-d O13 H9 M20 E2854a-d O14 H1 M20 E2855a-d O14 H2 M20 E2856a-d O14 H3 M20 E2857a-d O14 H4 M20 E2858a-d O14 H5 M20 E2859a-d O14 H6 M20 E2860a-d O14 H7 M20 E2861a-d O14 H8 M20 E2862a-d O14 H9 M20 E2863a-d O15 H1 M20 E2864a-d O15 H2 M20 E2865a-d O15 H3 M20 E2866a-d O15 H4 M20 E2867a-d O15 H5 M20 E2868a-d O15 H6 M20 E2869a-d O15 H7 M20 E2870a-d O15 H8 M20 E2871a-d O15 H9 M20 E2872a-d O16 H1 M20 E2873a-d O16 H2 M20 E2874a-d O16 H3 M20 E2875a-d O16 H4 M20 E2876a-d O16 H5 M20 E2877a-d O16 H6 M20 E2878a-d O16 H7 M20 E2879a-d O16 H8 M20 E2880a-d O16 H9 M20 E2881a-d O1 H1 M21 E2882a-d O1 H2 M21 E2883a-d O1 H3 M21 E2884a-d O1 H4 M21 E2885a-d O1 H5 M21 E2886a-d O1 H6 M21 E2887a-d O1 H7 M21 E2888a-d O1 H8 M21 E2889a-d O1 H9 M21 E2890a-d O2 H1 M21 E2891a-d O2 H2 M21 E2892a-d O2 H3 M21 E2893a-d O2 H4 M21 E2894a-d O2 H5 M21 E2895a-d O2 H6 M21 E2896a-d O2 H7 M21 E2897a-d O2 H8 M21 E2898a-d O2 H9 M21 E2899a-d O3 H1 M21 E2900a-d O3 H2 M21 E2901a-d O3 H3 M21 E2902a-d O3 H4 M21 E2903a-d O3 H5 M21 E2904a-d O3 H6 M21 E2905a-d O3 H7 M21 E2906a-d O3 H8 M21 E2907a-d O3 H9 M21 E2908a-d O4 H1 M21 E2909a-d O4 H2 M21 E2910a-d O4 H3 M21 E2911a-d O4 H4 M21 E2912a-d O4 H5 M21 E2913a-d O4 H6 M21 E2914a-d O4 H7 M21 E2915a-d O4 H8 M21 E2916a-d O4 H9 M21 E2917a-d O5 H1 M21 E2918a-d O5 H2 M21 E2919a-d O5 H3 M21 E2920a-d O5 H4 M21 E2921a-d O5 H5 M21 E2922a-d O5 H6 M21 E2923a-d O5 H7 M21 E2924a-d O5 H8 M21 E2925a-d O5 H9 M21 E2926a-d O6 H1 M21 E2927a-d O6 H2 M21 E2928a-d O6 H3 M21 E2929a-d O6 H4 M21 E2930a-d O6 H5 M21 E2931a-d O6 H6 M21 E2932a-d O6 H7 M21 E2933a-d O6 H8 M21 E2934a-d O6 H9 M21 E2935a-d O7 H1 M21 E2936a-d O7 H2 M21 E2937a-d O7 H3 M21 E2938a-d O7 H4 M21 E2939a-d O7 H5 M21 E2940a-d O7 H6 M21 E2941a-d O7 H7 M21 E2942a-d O7 H8 M21 E2943a-d O7 H9 M21 E2944a-d O8 H1 M21 E2945a-d O8 H2 M21 E2946a-d O8 H3 M21 E2947a-d O8 H4 M21 E2948a-d O8 H5 M21 E2949a-d O8 H6 M21 E2950a-d O8 H7 M21 E2951a-d O8 H8 M21 E2952a-d O8 H9 M21 E2953a-d O9 H1 M21 E2954a-d O9 H2 M21 E2955a-d O9 H3 M21 E2956a-d O9 H4 M21 E2957a-d O9 H5 M21 E2958a-d O9 H6 M21 E2959a-d O9 H7 M21 E2960a-d O9 H8 M21 E2961a-d O9 H9 M21 E2962a-d O10 H1 M21 E2963a-d O10 H2 M21 E2964a-d O10 H3 M21 E2965a-d O10 H4 M21 E2966a-d O10 H5 M21 E2967a-d O10 H6 M21 E2968a-d O10 H7 M21 E2969a-d O10 H8 M21 E2970a-d O10 H9 M21 E2971a-d O11 H1 M21 E2972a-d O11 H2 M21 E2973a-d O11 H3 M21 E2974a-d O11 H4 M21 E2975a-d O11 H5 M21 E2976a-d O11 H6 M21 E2977a-d O11 H7 M21 E2978a-d O11 H8 M21 E2979a-d O11 H9 M21 E2980a-d O12 H1 M21 E2981a-d O12 H2 M21 E2982a-d O12 H3 M21 E2983a-d O12 H4 M21 E2984a-d O12 H5 M21 E2985a-d O12 H6 M21 E2986a-d O12 H7 M21 E2987a-d O12 H8 M21 E2988a-d O12 H9 M21 E2989a-d O13 H1 M21 E2990a-d O13 H2 M21 E2991a-d O13 H3 M21 E2992a-d O13 H4 M21 E2993a-d O13 H5 M21 E2994a-d O13 H6 M21 E2995a-d O13 H7 M21 E2996a-d O13 H8 M21 E2997a-d O13 H9 M21 E2998a-d O14 H1 M21 E2999a-d O14 H2 M21 E3000a-d O14 H3 M21 E3001a-d O14 H4 M21 E3002a-d O14 H5 M21 E3003a-d O14 H6 M21 E3004a-d O14 H7 M21 E3005a-d O14 H8 M21 E3006a-d O14 H9 M21 E3007a-d O15 H1 M21 E3008a-d O15 H2 M21 E3009a-d O15 H3 M21 E3010a-d O15 H4 M21 E3011a-d O15 H5 M21 E3012a-d O15 H6 M21 E3013a-d O15 H7 M21 E3014a-d O15 H8 M21 E3015a-d O15 H9 M21 E3016a-d O16 H1 M21 E3017a-d O16 H2 M21 E3018a-d O16 H3 M21 E3019a-d O16 H4 M21 E3020a-d O16 H5 M21 E3021a-d O16 H6 M21 E3022a-d O16 H7 M21 E3023a-d O16 H8 M21 E3024a-d O16 H9 M21 E3025a-d O1 H1 M22 E3026a-d O1 H2 M22 E3027a-d O1 H3 M22 E3028a-d O1 H4 M22 E3029a-d O1 H5 M22 E3030a-d O1 H6 M22 E3031a-d O1 H7 M22 E3032a-d O1 H8 M22 E3033a-d O1 H9 M22 E3034a-d O2 H1 M22 E3035a-d O2 H2 M22 E3036a-d O2 H3 M22 E3037a-d O2 H4 M22 E3038a-d O2 H5 M22 E3039a-d O2 H6 M22 E3040a-d O2 H7 M22 E3041a-d O2 H8 M22 E3042a-d O2 H9 M22 E3043a-d O3 H1 M22 E3044a-d O3 H2 M22 E3045a-d O3 H3 M22 E3046a-d O3 H4 M22 E3047a-d O3 H5 M22 E3048a-d O3 H6 M22 E3049a-d O3 H7 M22 E3050a-d O3 H8 M22 E3051a-d O3 H9 M22 E3052a-d O4 H1 M22 E3053a-d O4 H2 M22 E3054a-d O4 H3 M22 E3055a-d O4 H4 M22 E3056a-d O4 H5 M22 E3057a-d O4 H6 M22 E3058a-d O4 H7 M22 E3059a-d O4 H8 M22 E3060a-d O4 H9 M22 E3061a-d O5 H1 M22 E3062a-d O5 H2 M22 E3063a-d O5 H3 M22 E3064a-d O5 H4 M22 E3065a-d O5 H5 M22 E3066a-d O5 H6 M22 E3067a-d O5 H7 M22 E3068a-d O5 H8 M22 E3069a-d O5 H9 M22 E3070a-d O6 H1 M22 E3071a-d O6 H2 M22 E3072a-d O6 H3 M22 E3073a-d O6 H4 M22 E3074a-d O6 H5 M22 E3075a-d O6 H6 M22 E3076a-d O6 H7 M22 E3077a-d O6 H8 M22 E3078a-d O6 H9 M22 E3079a-d O7 H1 M22 E3080a-d O7 H2 M22 E3081a-d O7 H3 M22 E3082a-d O7 H4 M22 E3083a-d O7 H5 M22 E3084a-d O7 H6 M22 E3085a-d O7 H7 M22 E3086a-d O7 H8 M22 E3087a-d O7 H9 M22 E3088a-d O8 H1 M22 E3089a-d O8 H2 M22 E3090a-d O8 H3 M22 E3091a-d O8 H4 M22 E3092a-d O8 H5 M22 E3093a-d O8 H6 M22 E3094a-d O8 H7 M22 E3095a-d O8 H8 M22 E3096a-d O8 H9 M22 E3097a-d O9 H1 M22 E3098a-d O9 H2 M22 E3099a-d O9 H3 M22 E3100a-d O9 H4 M22 E3101a-d O9 H5 M22 E3102a-d O9 H6 M22 E3103a-d O9 H7 M22 E3104a-d O9 H8 M22 E3105a-d O9 H9 M22 E3106a-d O10 H1 M22 E3107a-d O10 H2 M22 E3108a-d O10 H3 M22 E3109a-d O10 H4 M22 E3110a-d O10 H5 M22 E3111a-d O10 H6 M22 E3112a-d O10 H7 M22 E3113a-d O10 H8 M22 E3114a-d O10 H9 M22 E3115a-d O11 H1 M22 E3116a-d O11 H2 M22 E3117a-d O11 H3 M22 E3118a-d O11 H4 M22 E3119a-d O11 H5 M22 E3120a-d O11 H6 M22 E3121a-d O11 H7 M22 E3122a-d O11 H8 M22 E3123a-d O11 H9 M22 E3124a-d O12 H1 M22 E3125a-d O12 H2 M22 E3126a-d O12 H3 M22 E3127a-d O12 H4 M22 E3128a-d O12 H5 M22 E3129a-d O12 H6 M22 E3130a-d O12 H7 M22 E3131a-d O12 H8 M22 E3132a-d O12 H9 M22 E3133a-d O13 H1 M22 E3134a-d O13 H2 M22 E3135a-d O13 H3 M22 E3136a-d O13 H4 M22 E3137a-d O13 H5 M22 E3138a-d O13 H6 M22 E3139a-d O13 H7 M22 E3140a-d O13 H8 M22 E3141a-d O13 H9 M22 E3142a-d O14 H1 M22 E3143a-d O14 H2 M22 E3144a-d O14 H3 M22 E3145a-d O14 H4 M22 E3146a-d O14 H5 M22 E3147a-d O14 H6 M22 E3148a-d O14 H7 M22 E3149a-d O14 H8 M22 E3150a-d O14 H9 M22 E3151a-d O15 H1 M22 E3152a-d O15 H2 M22 E3153a-d O15 H3 M22 E3154a-d O15 H4 M22 E3155a-d O15 H5 M22 E3156a-d O15 H6 M22 E3157a-d O15 H7 M22 E3158a-d O15 H8 M22 E3159a-d O15 H9 M22 E3160a-d O16 H1 M22 E3161a-d O16 H2 M22 E3162a-d O16 H3 M22 E3163a-d O16 H4 M22 E3164a-d O16 H5 M22 E3165a-d O16 H6 M22 E3166a-d O16 H7 M22 E3167a-d O16 H8 M22 E3168a-d O16 H9 M22

3. SYNTHESIS OF THE COMPOUNDS OF THE INVENTION

In another aspect, the invention provides methods for making the compounds of the invention. The following schemes depict some exemplary chemistries available for synthesizing the compounds of the invention. It will be appreciated, however, that the desired compounds may be synthesized using other alternative chemistries known in the art.

Scheme 1 illustrates the synthesis of oxazolidinones substituted at C-5 with 1,2,3-triazolylmethyl derivatives. Isocyanates 14 can react with lithium bromide and glycidyl butyrate at elevated temperature to produce oxazolidinone intermediates of type 15 (Gregory et al. (1989) J. MED. CHEM. 32:1673). Hydrolysis of the resulting butyrate ester of compound 15 produces alcohol 17. Alcohol 17 can also be synthesized from carbamates such as the benzyl carbamate 16. The carbamate nitrogen of compound 16 then is deprotonated, and alkylated with glycidyl butyrate to produce (after in situ hydrolysis of the butyl ester) hydroxymethyl derivative 17. While the R enantiomer depicted throughout Scheme 1 generally is the most biologically useful derivative for antibacterial agents, it is contemplated that compounds derived from either the R or the S enantiomer, or any mixture of R and S enantiomers, may be useful in the practice of the invention.

Alcohols 17 can be converted to useful intermediates such as mesylates 18a (by treatment with methanesulfonyl chloride and triethylamine in an appropriate solvent) and azide 19 (by subsequent displacement of the mesylate by sodium azide in DMF). Azide 19 can also be produced from tosylate 18b (or a brosylate or nosylate), or an alkyl halide of type 18c (made from alcohol 17 via methods known to those skilled in the art). Azide 19 can be heated in the presence of substituted acetylenes 20 to produce C-5 substituted 1,2,3-triazolylmethyl oxazolidinone derivatives of type 21 and 22. It is to be understood that alternative chemical conditions could be employed by those skilled in the art to effect this transformation.

It is understood that unsymmetrical acetylene derivatives can react to produce a mixture of regioisomeric cycloaddition products, represented by 21 and 22, and that the reaction conditions can be adjusted by processes known to those skilled in the art to produce more selectively one regioisomer or the other. For example, Scheme 2 depicts the reaction of mono-substituted acetylene 23 with azide 19 to produce two regioisomeric triazoles, 24 and 25. The major isomer is most often the anti isomer 24 since the reaction leading to this product proceeds at a faster rate. Under certain circumstances, the more sterically disfavored syn isomer is also formed, but at an appreciably diminished rate. The addition of copper(I)iodide is a useful additive for this reaction, and often leads to increased proportions of the major “anti” adduct 24 (Tomoe, C. W. et al. (2002) J. ORG. CHEM. 67: 3057). Increased proportions of the minor isomer 25 may be produced by minor modification of the reaction scheme. Azide 19 can react with the trimethylsilyl substituted acetylene 26 to produce the anti isomer 27 and the syn isomer 28. Desilylation with tetrabutylammonium fluoride can produce triazole 24 and 25, with increased proportions of 25 obtainable from the more abundant precursor triazole 27.

An alternate approach toward the synthesis of some of the compounds of the present invention is shown in Scheme 3. Aromatic halide 29, when activated, can react with the anion derived from treatment of carbamate 33 with an appropriate base to produce 3-aryl substituted oxazolidinone derivatives 31 via nucleophilic aromatic substitution. Suitable bases include, for example, n-BuLi, LiN(Si(CH₃)₃)₂, and NaH. Carbamate 33 can be synthesized by exposure of 32 to carbonyldiimidazole in DMF, followed by in situ silylation of the hydroxymethyl group of the initial product with an appropriate silyl chloride. Desilylation of derivatives of type 31 produces alcohols 17 that can be converted to the targets of the present invention by the processes described within the schemes.

Scheme 4a illustrates the synthesis of some alkynes of type 23 required for the synthesis of some of the compounds of the present invention. Secondary alkyl amines (or cycloalkyl amines) can be alkylated with electrophiles comprised of an alkyne connected by a variable bond or linker to a carbon bearing a leaving group, for example, a halide or sulfonate group (35), to produce alkynes of type 36. The substituted alkynes can be used in cycloaddition reactions with azides to yield triazole-linked target compounds. The amino group undergoing such an alkylation can be derived from amino saccharides, for example (but not limited to), the des-methyl desosamine derivative 37. Desosamine derivative 37 is available from the degradation of erythromycin. Alkylation of 37 with alkynes 35 produces triazole-linked sugar compounds of type 38. The dimethyl amino group of the desosamine sugar of macrolide antibiotics can be monodemethylated to produce the corresponding secondary amine (U.S. Pat. No. 3,725,385, Flynn et al. (1954) J. AM. CHEM. SOC. 76: 3121; Ku et al. (1997) BIOORG. MED. CHEM. LETT. 7: 1203; Stenmark et al. (2000) J. ORG. CHEM. 65: 3875). For example, amine 39 (an intermediate in the synthesis of amino sugar 37), or a suitably protected derivative of 39 such as the per-silylated compound (formed by pre-treatment with bis-trimethylsilylacetamide, hexamethyldisilazane or other agents known in the art) can be alkylated with alkynes of type 35. This alkylation reaction produces intermediates of type 40, that can react with azides of type 19 to yield target compounds.

An alternative route is available for the production of desosamine derivatives 38. Alkynes 40 can be hydrolyzed with strong acid to produce amines 38. It is understood that, given appropriate reaction conditions known to those skilled in the art, any macrolide antibacterial agent (naturally occurring, semi-synthetic or synthesized) is capable of serving as starting material for the processes depicted in Scheme 4a.

Scheme 4b illustrates the synthesis of compounds of the present invention that contain extra keto groups in the alkyl link between the 5-membered heterocyclic ring and the macrolide moiety. Azides 19 can react with propiolate esters to produce the ester-substituted products. (It is to be understood that mixtures of regioisomeric cycloadducts may form in this reaction, however, only the anti adduct is depicted in Scheme 4b.) Hydrolysis of the ester yields the acid, which can be converted using known chemistry (Ramtohul et al. (2000) J. ORG. CHEM. 67: 3169) to the bromoacetyl triazole. Heating this bromoacetyl derivative with 39 (or a suitably protected version of 39) can yield products that contain a keto link with one methylene group between the ketone and the macrolide group. The bromoacetyl intermediate can be converted via lithio-dithiane chemistry, subsequent hydrolysis, and reduction to an alcohol. The tosylate (or halide) of this alcohol can be made, and this electrophile can be used to alkylate 39 to give products with two methylene groups between the ketone and the macrolide group.

Scheme 5 illustrates another method to synthesize regioisomeric triazole-linked derivatives of the invention. Carbon-linked triazole derivatives of type 44 and 45 can be produced by first displacing a leaving group (for example, a sulfonate or a halide) from electrophiles 18a-c, with either lithium acetylide 41a or lithium trimethylsilylacetylide 41b to produce alkynes 42. The cycloaddition reaction of alkynes 42 with appropriate azides 43 can yield regioisomeric triazoles 44 and 45. (It will be understood that alternative chemical conditions could be employed to produce compounds 44 and 45 such as the use of copper(I) iodide instead of heat).

A specific example of the utility of the chemistry expressed in Scheme 5 is shown in Scheme 6. Des-methyl erythromycin derivative 39 (or a suitably protected derivative thereof) can be alkylated with a bromoalcohol, and the alcohol function of the product converted to a leaving group such as a tosylate. The tosylate can be displaced with sodium azide to yield azide 46. Cycloadditon of 46 and alkyne 42a can produce final targets of type 47. Alternative alkylsulfonates or halides can be used as the starting material for the synthesis of azide 46 (i.e., different leaving groups). Other macrolide entities can be used in place of the des-methyl erythromycin derivative 39 to produce a variety of alternative products.

Another method that can be used to synthesize carbon-linked triazole derivatives of type 47 is illustrated in Scheme 7. Alkyne 42a can react with trimethylsilylazide (or with sodium azide, ammonium chloride and copper(I) iodide, or other conditions known in the art) to produce two possible regioisomeric products, triazoles 48 and 49. Either of these (or the mixture) can be desilylated with n-Bu₄NF to produce triazole 50. Des-methyl erythromycin derivative 39 (or an alternate des-methyl amino macrolide derivative) can be converted to tosylate 51 (or another sulfonate or halide electrophile), and then the electrophile can serve to alkylate triazole 50 to produce either the N−1 substituted triazole 47, or the N-2 substituted triazole 53, or a mixture of both. In the event that a mixture is produced, both compounds may be separated from one another. It is contemplated that other macrolides may be transformed by the chemistry of Scheme 7 to produce other compounds of interest.

Scheme 8a illustrates the synthesis of oxazolidinones substituted at C-5 with tetrazolylmethyl derivatives. Azides of type 19 can react with nitrites 54 to produce tetrazoles of type 55 and 56. In a similar fashion to the chemistry described in Scheme 1, this reaction can yield regioisomeric cycloadducts, where the anti isomer often predominates. As an example, des-methyl erythromycin 39 can be alkylated with co-halo or co-sulfonate nitrites to yield nitrites 57. These derivatives can react with azides of type 19 to produce target tetrazoles of type 59 and 60. It is to be understood that the R′ group of nitrites 54 may contain the macrolide moiety, or suitable substituted alkyl groups containing an alcohol or protected alcohol that could be converted to a leaving group prior to a final alkylation step with a macrolide amine. Thus, the tetrazoles 55 and 56 could be produced that have as their R′ groups alkyl chains bearing a hydroxy group that can be converted into a sulfonate or halide leaving group prior to alkylation with amines similar to 39 to afford products of type 59 and 60. The hydroxy group may be unmasked from a protected hydroxyl group in the compounds 55 and 56 prior to further conversions as mentioned above to afford targets of type 59 and 60.

Scheme 8b depicts another strategy to synthesize tetrazoles of type 59 and 60. Azides 19 could undergo cycloaddition to functionalized nitriles of type 57a to afford tetrazole intermediates 55a and 56a. If 55a and 56a contain an appropriate electrophilic group such as a halide or sulfonate, it can react directly with macrolide amines of type 39 (or a suitably protected 110 derivative thereof) to yield targets of type 59 and 60. Alternatively, silyloxy-substituted nitriles 57a could be used during the cycloaddition reaction to afford intermediates of type 55a and 56a where X is a silyloxy group. The silylether protecting group could then be removed from 55a and 56a, and the resultant alcohol converted to an appropriate electrophile (such as a halide or sulfonate) that would then be suitable for alkylation of macrolide amines of type 39 to give the desired targets.

It will be understood that if the alkyl group bearing substituent X in 55a and 56a contains a hydroxyl group, the group could be oxidized to an aldehyde by methods well known to those skilled in the art. Such aldehydes could be used to produce targets of type 59 and 60 via the use of reductive amination conditions employed on these aldehydes and macrolide amines similar to amine 39 (or suitably protected variants thereof).

Scheme 9 illustrates one method of synthesizing pyrazole derivatives of the present invention. Known trityl-protected organolithium derivative 61 (Elguero et al. (1997) SYNTHESIS 563) can be alkylated with electrophiles of type 18a-c to produce pyrazoles of type 62. Cleavage of the trityl group can be accomplished using a variety of acidic reagents, for example, trifluoroacetic acid (TFA), to produce pyrazole 63. Alkylation of 63 with a bromoalcohol of appropriate length, followed by tosylation (or alternate sulfonation or halide formation) can produce electrophiles 64. Alkylation of 39 with 64 produces targets of type 65. The lithium anions derived from heterocycles such as 61 may optionally be converted to copper (or other metallic) derivatives to facilitate their displacement reactions with sulfonates and halides. These anions may also be allowed to react with suitably protected macrolides, such as the per-silylated derivative of 51.

Scheme 10 depicts another method of synthesizing pyrazoles of the present invention. Anions 61 can be alkylated with a bifunctional linker of variable length such as an alkyl halide containing a silyloxy derivative. Alternatively an α,ω dihaloalkyl derivative can be used as the alkylating agent, or a mixed halo-sulfonate can be employed for this purpose. The resulting substituted pyrazoles 66 can be converted to the free pyrazoles by TFA cleavage of the triphenylmethyl protecting group. The free pyrazoles can undergo direct alkylation with electrophiles 18a-c in a suitable solvent, for example, dimethylformamide, or can be first converted via deprotonation with a suitable base, for example, sodium hydride or n-butyllithium, to the corresponding anion, if a more reactive nucleophile is required. The resultant pyrazole derivatives 67 can be desilylated and converted to tosylates 68 (if a sulfonate strategy is employed), which can serve as electrophiles for subsequent reaction with macrolide aminosaccharides, for example, amine 39, to produce the resultant target 69.

Another approach to intermediates of type 67 can start with alkylation of the known dianion 70 (Hahn et al. (1991) J. HETEROCYCLIC CHEMISTRY 28:1189) with an appropriate bifunctional linker to produce compounds related to pyrazole 71, which can subsequently be alkylated (with or without prior deprotonation) with electrophiles 18a-c to produce intermediates 67. The n=1 derivatives in this series can be synthesized by trapment of compound 61 with DMF to produce the corresponding aldehyde, and then reduction to the alcohol. Alternatively, methoxymethyl (MOM) chloride or bromide can serve as the alkylating reagent for 61, and hydrolysis of the trityl and MOM groups of the product would yield 4-hydroxymethyl-1,2-pyrazole. The dianion of this pyrazole can be alkylated on nitrogen to produce an alcohol that serves as the precursor for a n=1 tosylate (or other leaving group).

Scheme 11 shows an alternate approach for synthesizing pyrazole derivatives of type 69. Alkylation of the anion of a β-dicarbonyl system with appropriate electrophiles similar to tosylate 51 can yield (in the specific example of β-dicarbonyl derivative 72a) products of type 73. Treatment of these intermediates with hydrazine can produce pyrazoles of type 74. Direct alkylation of 74 with electrophiles 18a-c can proceed to produce targets 69. Alternatively, the hydroxyl residues of 74 (and other sensitive functional groups of other macrolide derivatives such as intermediates 39 and 51) can be protected with suitable protecting groups (such as those highlighted in Greene, T. W. and Wuts, P. G. M. supra), and the hydrogen atom on the nitrogen atom of the pyrazole derivative deprotonated with a suitable base, for example, sodium hydride or n-butyllithium. The resulting anion can then be alkylated with electrophiles 18a-c, and the resulting product deprotected to produce targets 69. The use of protecting groups well known to those skilled in the art for the macrolide portions of these intermediates may be required for many of the subsequent reactions shown in the schemes below that involve heteroaryl anion alkylations.

Scheme 12 exemplifies a synthesis of imidazoles of the present invention. The known dianion 75 (Katritzky et al. (1989) J. CHEM. SOC. PERKIN TRANS. 1: 1139) can react with electrophiles 18a-c to produce after protic work-up imidazoles of type 76. Direct alkylation of 76 by heating with electrophiles related to 51 in an appropriate organic solvent can yield 1,4-disubstituted imidazoles 77. Alternatively, the imidazole anion formed via deprotonation of the imidazole hydrogen atom of 76 with a suitable base and then alkylation with 51 can also produce 77.

Scheme 13 illustrates another synthesis of imidazoles of the present invention. 4-Bromoimidazole can be deprotonated using, for example, sodium hydride or lithium diisopropylamide, or another suitable organic base, to give anion 78 (or the corresponding lithio derivative). Alkylation of 78 with 18a-c can yield bromoimidazole 79 which can then be subjected to metal-halogen exchange and alkylated with 51 (or a suitably protected derivative of 51) to produce isomeric 1,4-disubstituted imidazoles 80.

Scheme 14 depicts chemistry suitable for the synthesis of other target imidazole derivatives. The silylethoxymethyl (SEM) protected imidazole can be lithiated at C-2 (Shapiro et al. (1995) HETEROCYCLES 41: 215) and can react with electrophiles 18a-c to produce imidazole intermediates 82. Lithiation of imidazole intermediates 82 at C-4 of the imidazole, followed by alkylation with electrophiles of type 51 (or a suitably protected version such as the per-silylated derivative), and then deprotection of the SEM can produce imidazoles 83.

Scheme 15 shows how tosylmethyl isocyanide can be used to make imidazoles of the present invention (Vanelle et al. (2000) EUR. J. MED. CHEM. 35: 157; Home et al. (1994) HETEROCYCLES 39: 139). Alcohols 17 can be oxidized to produce aldehydes 85 using an appropriate agent such as the Dess-Martin periodinane, or oxalyl chloride/dimethylsulfoxide/triethylamine (Swern oxidation). A variety of chromium complexes can also be used for this oxidation, including, for example, pyridinium dichromate (PDC), pyridinium chlorochromate (PCC), chromium trioxide, and tetrapropylammonium perruthenate. Wittig homologation of 85 can provide aldehyde 86, which can then be converted by tosylmethyl isocyanide to produce intermediate 87. The reaction of 87 with amines 89 (formed via alkylation of amines 39 with bromoalkyl phthalimides 88 followed by hydrazine cleavage, or reduction of azides 46) can produce imidazoles 77.

Scheme 16 delineates how 1,3 thiazole and 1,3 oxazole derivatives of the present invention can be synthesized. Known dibromo thiazoles and oxazoles 90a and 90b can be selectively metallated at C-2 and alkylated with electrophiles 18a-c to produce intermediates 91a and 91b (Pinkerton et al. (1972) J. HETEROCYCLIC CHEMISTRY 9: 67). Transmetallation with zinc chloride can be employed in the case of the oxazole anion if the anion displays any tendency to ring open prior to its reaction with certain electrophiles. The bromo azoles 91 can be metallated to form the corresponding anion which can undergo alkylation with sulfonates 51 (or the related halides) to produce the final targets 92. Reordering of the sequence of electrophiles in this process permits access to the isomeric thiazoles and oxazoles 93.

Scheme 17 shows the synthesis of 2,5 disubstituted furan and thiophene derivatives of the invention. Commercially available dibromofuran 94a and dibromothiophene 94b can be monolithiated (Chemoux et al. (2001) ADVANCED FUNCTIONAL MATERIALS 11: 305) and alkylated with electrophiles 18a-c. The monobromo intermediates obtained from this reaction can be lithiated again and then alkylated with electrophiles of type 51 (or a protected version of 51) to produce the final targets 95.

Scheme 18 depicts the synthesis of 2,4 disubstituted furan and thiophene derivatives of the invention. Commercially available furan aldehyde 96a, and the known thiophene aldehyde 96b, can be reduced to the corresponding alcohols and the resulting alcohols converted to a leaving group such as tosylates 97. Alternate sulfonates and halides can be synthesized and used in this fashion. The tosylates 97 can alkylate amine 39 (or a protected version thereof), and the heteroaryl bromide can be converted to a suitable organometallic agent (by reagents such as n-BuLi, or i-Pr₂Mg/CuCN). This intermediate organometallic agent can be alkylated with electrophiles 18a-c to produce targets of type 98 where n=1. As the scheme shows, a reordering of steps can be employed involving reduction, silylation, lithiation and then initial alkylation with 18a-c. Desilylation of the alkylation product, followed by tosylation of the alcohol, provides an intermediate that can then be alkylated with amine 39 to produce targets 98. Simple homologation protocols, using the reagents depicted in Scheme 18 or others known to those skilled in the art, can convert the aldehydes 96 to longer chain tosylates such as 99 and 100. The use of these tosylates in the alkylation with 39, and subsequent metal-halogen exchange and alkylation with 18a-c, can yield compounds of type 98 where n=2 and 3. It will be appreciated that longer chain tosylates can be produced using chemistries similar to that depicted in Scheme 18, and that other bifunctional linkers can be used to produce compounds of type 98.

Chemistries similar to that employed above in Scheme 18 can convert known thiophene aldehyde 101 (Eras et al. (1984) J. HETEROCYCLIC CHEMISTRY 21: 215) to produce products of type 104 (Scheme 19). The known acid 102 (Wang et al. (1996) TETRAHEDRON 52: 12137) can be converted to aldehyde 103 by reduction with, for example, borane or lithium aluminum hydride, followed by oxidation of the resultant hydroxymethyl intermediate with, for example, PDC, PCC, or another suitable reagent. Aldehyde 103 can then be converted to produce compounds of type 104.

Scheme 20 illustrates the synthesis of 2,5 disubstituted pyrroles of the invention. The BOC-protected dibromopyrrole 105 can be lithiated and alkylated sequentially (Chen et al. (1987) TETRAHEDRON LETT. 28: 6025; Chen et al. (1992) ORG. SYNTH. 70:151; and Martina et al. (1991) SYNTHESIS 613), and allowed to react with electrophiles 18a-c and 51 (or a suitably protected analogue of 51) to produce, after final BOC deprotection with TFA, disubstituted pyrroles of type 106.

Scheme 21 shows the synthesis of 2,4 disubstituted pyrroles of the invention. Commercially available pyrrole ester 107 can be protected with a suitable protecting group, for example, the BOC group, and the ester function hydrolyzed to the corresponding acid. The resulting acid can then be reduced to the alcohol using, for example, borane to yield an alcohol that can be converted to tosylate 108. Amine 39 (or a suitably protected version of 39, formed for example by silylation of the hydroxyl groups with bis-trimethylsilylacetamide or another silylating reagent) can be alkylated with tosylate 108 to produce an intermediate bromopyrrole. The bromopyrrole can then be converted to an organometallic reagent that can then react with electrophiles 18a-c. The resulting product can then be deprotected with TFA to produce pyrroles 109. The alcohol formed after borane reduction of the acid derived from 107 can then be homologated to tosylates 110 and 111 by chemistries similar to that shown below in Scheme 23. The use of these tosylates in the alkylation strategy can produce target pyrroles of type 109 where n=2 and 3.

An alternative approach is to protect the alcohol functions prior to tosylation, and perform the alkylation of the organometallic derived from the halopyrrole with 18a-c first. For example, silyloxy derivative 112 can be produced from 107, and the organometallic derivative derived from it alkylated with 18a-c to yield silyl ethers 113. Subsequent desilylation and conversion to tosylates 114 provides an electrophile that can be used in the alkylation reaction with 39. A final BOC cleavage can then give pyrroles 109. It is understood that the alcohol precursor of 112 can be homologated, using chemistries similar to that shown below in Scheme 23 and other schemes) to other alkanols that can be tosylated for further reactions with amine 39 (or related macrolide derived amines). Furthermore, the alcohol derived from silyl cleavage of 113 can serve as the starting material for this type of homologation efforts to produce the alkyl tosylates (or halides) required for making targets 109 where n is variable.

Scheme 22 shows the synthesis of isomeric 2,4 disubstituted pyrroles of the invention. Commercially available pyrrole acid 115 can be protected as the BOC derivative, and the acid function reduced to an alcohol, which can then be protected to produce the silyl ether 116. Deprotonation of 116 with n-butyllithium can occur at the 5 position of the pyrrole ring, and this anion (or that derived from transmetallation with an appropriate metal) can be alkylated with electrophiles 18a-c to produce pyrrole 117. Desilylation of 117, followed by tosylation, alkylation with amine 39, and TFA deprotection of the BOC group can yield pyrroles 119.

Scheme 23 illustrates the synthesis of longer chain tosylates of type 123 and 126 used to alkylate amines of type 39 to produce pyrroles 119. The alcohol 120 derived from protection of 115 followed by borane reduction can be oxidized to aldehyde 124. The Wittig reaction of aldehyde 124 with methoxymethyl triphenylphosphorane is followed by an acid hydrolysis step to produce the homologated aldehyde 121. Reduction and silyl protection can yield 122, which can then be deprotonated, alkylated and then converted to tosylate 123. Aldehyde 124 can undergo a Wittig reaction with carbomethoxymethyl triphenylphosphorane. The Wittig product then is reduced to an alkanol that can then be silylated to produce 125. Conversion of 125 to pyrroles 119 can then occur using the same chemistry employed to provide 119 from 122.

Scheme 24 shows the synthesis of 1,3 disubstituted pyrroles of the present invention. The BOC group of 116 can be cleaved to produce free pyrrole 127. Alkylation of 127 (in a suitable organic solvent such as DMF) with 18a-c can produce intermediate 128. The dianion of 3-hydroxymethylpyrrole can also be suitable for alkylation with 18a-c to produce the free hydroxy derivative of silyl ether 128. Conversion of the siloxy group to the corresponding tosylate, followed by alkylation with amines of type 39 can generate the target N-substituted pyrroles 129 (where n=1). In a similar fashion, the BOC pyrroles 122 and 125 can be converted to the tosylates 130 and 131. These tosylates can be used to produce pyrroles of type 129 (where n=2 and 3). It is understood that longer chain alkyl tosylates (and halides) can be produced that can undergo this chemistry to produce pyrroles 129 where n is >3.

Scheme 25 illustrates the use of hydantoin-like groups as the 5-membered heterocyclic linker between the G groups and the R¹ moieties of the present invention. Electrophiles of type 18a-c can alkylate anions derived from hydantoins to produce compounds of the present invention. For example, 3-substituted hydantoins of type 132 can be purchased and treated with an appropriate base to generate the corresponding imide anion. The resulting anions can be alkylated with electrophiles similar (but not limited) to intermediates 18a-c to produce hydantoin derivatives 134. Alternatively, 1-substituted hydantoins of type 133 can be purchased or prepared, and treated with base and electrophile to yield isomeric hydantoin derivatives 135. It is understood that such hydantoins can have, for example, at optional locations, thiocarbonyl functionalities in place of the illustrated carbonyl groups. Such compounds can be prepared by treatment of the oxy-hydantoins with Lawesson's reagent, elemental sulfur, phosphorus pentasulfide, and other reagents commonly used in the art to perform this transformation.

Alternatively, such thiohydantoins can be synthesized selectively by sequential synthetic steps known in the art. The R′ group of 132 and 133 may represent a protecting group function, for example, benzyl, alkoxybenzyl, benzyloxycarbonyl, t-butoxycarbonyl, that is compatible with the alkylation step. Such a protecting group can subsequently be removed from products 134 and 135, yielding products where the R′ group is a hydrogen atom. These intermediates can be used to produce various target molecules by their treatment with base and then subsequent exposure to appropriate electrophiles.

A more specific example of the synthesis of hydantoin derivatives of the present invention is depicted in Scheme 26. Hydantoin 136 can be treated with a mild organic base, for example, sodium hydride, potassium tertiary-butoxide, cesium, sodium, or potassium carbonate, to produce the N−1 substituted intermediate 137. Deprotonation of 137 with a base, for example, sodium hydride, n-butyllithium, lithium bis-trimethylsilylamide or lithium diisopropylamide, followed by alkylation with 51 (or a suitably protected derivative of 51) can yield hydantoin targets of type 138. The isomeric hydantoin derivatives of type 141 can be synthesized from 136 by initial p-methoxybenzyl (PMB) protection of the N−1 position, followed by alkylation at N-3 with 18a-c and subsequent deprotection of the PMB group with either 2,3-dichloro-3,4-dicyano-benzoquinone (DDQ) or hydrogenation will yield hydantoin intermediates 140. Subsequent alkylation of 140 with 51 can give compounds 141. Another route to produce intermediates 140 is by formation of the dianion of hydantoin 136. One equivalent of a weak base can deprotonate the N−1 position of 136. The addition of another equivalent of a strong base, for example, n-butyllithium, to the initial anion can deprotonate it again, this time at N-3. Alkylation can occur at the more reactive position (N-3) to again produce hydantoins 140.

Scheme 27 illustrates how isoxazolidinone derivatives of type 515 of the present invention can be synthesized. Macrolide 171 (or any other macrolide amine) can be converted to alkyl azide 510 (where n≧2) via use of an appropriate alkyl halide or sulfonate electrophile of type 511. A variety of isoxazolidinone derivatives of type 512 (for syntheses of these types of derivatives see US Patent Application 20020094984) can be alkylated with propargyl electrophiles of type 513 to yield alkynes of type 514. The cycloaddition of azides 510 and alkynes 514 yields target isoxazolidinone derivatives 515. It is to be understood that alternative macrolides and isoxazolidinone derivatives can be used in this chemistry, and alternate chain lengths of the various electophiles can be utilized to produce other compounds of the present invention. It is intended that such alternate targets are within the scope of the present invention.

In addition to the foregoing, compounds disclosed in the following publications, patents and patent applications are suitable intermediates for preparation of the compounds of this invention:

Tucker, J. A. et al., J. Med. Chem., 1998, 41, 3727; Gregory, W. A. et al., J. Med. Chem., 1990, 33, 2569; Genin, M. J. et al., J. Med. Chem., 1998, 41, 5144; Brickner, S. J. et al., J. Med. Chem., 1996, 39, 673. Barbachyn, M. R. et al., J. Med. Chem., 1996, 39, 680; Barbachyn, M. R. et al., Bioorg. Med. Chem. Lett., 1996, 6, 1003; Barbachyn, M. R. et al., Bioorg. Med. Chem. Lett., 1996, 6, 1009; Grega, K. C. et al., J. Org. Chem., 1995, 60, 5255; Park, C.-H. et al., J. Med. Chem., 1992, 35, 1156; Yu, D. et al., Bioorg. Med. Chem. Lett., 2002, 12, 857; Weidner-Wells, M. A. et al., Bioorg Med. Chem., 2002, 10, 2345; and Cacchi, S. et al., Org. Lett., 2001, 3, 2539. U.S. Pat. Nos. 4,801,600; 4,948,801; 5,736,545; 6,362,189; 5,523,403; 4,461,773; 6,365,751; 6,124,334; 6,239,152; 5,981,528; 6,194,441; 6,147,197; 6,034,069; 4,990,602; 6,124,269; and 6,271,383. U.S. Pat. Application 2001/0046992, PCT Application and publications WO96/15130; WO95/14684; WO 99/28317; WO 98/01447; WO 98/01446; WO 97/31917; WO 97/27188; WO 97/10223; WO 97/09328; WO 01/46164; WO 01/09107; WO 00/73301; WO 00/21960; WO 01/81350; WO 97/30995; WO 99/10342; WO 99/10343; WO 99/64416; WO 00/232917; and WO 99/64417, European Patents EP 0312000 B1; EP 0359418 A1; EP 00345627; EP 1132392; and EP 0738726 A1.

4. CHARACTERIZATION OF COMPOUNDS OF THE INVENTION

Compounds designed, selected and/or optimized by methods described above, once produced, may be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules may be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.

Furthermore, high-throughput screening may be used to speed up analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein for activity, for example, as anti-cancer, anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also, it may be possible to assay how the compounds interact with a ribosome or ribosomal subunit and/or are effective as modulators (for example, inhibitors) of protein synthesis using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

(1) Surface Binding Studies. A variety of binding assays may be useful in screening new molecules for their binding activity. One approach includes surface plasmon resonance (SPR) which can be used to evaluate the binding properties molecules of interest with respect to a ribosome, ribosomal subunit or a fragment thereof.

SPR methodologies measure the interaction between two or more macromolecules in real-time through the generation of a quantum-mechanical surface plasmon. One device, (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscatawy, N.J.) provides a focused beam of polychromatic light to the interface between a gold film (provided as a disposable biosensor “chip”) and a buffer compartment that can be regulated by the user. A 100 nm thick “hydrogel” composed of carboxylated dextran which provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film. When the focused light interacts with the free electron cloud of the gold film, plasmon resonance is enhanced. The resulting reflected light is spectrally depleted in wavelengths that optimally evolved the resonance. By separating the reflected polychromatic light into its component wavelengths (by means of a prism), and determining the frequencies which are depleted, the BIAcore establishes an optical interface which accurately reports the behavior of the generated surface plasmon resonance. When designed as above, the plasmon resonance (and thus the depletion spectrum) is sensitive to mass in the evanescent field (which corresponds roughly to the thickness of the hydrogel). If one component of an interacting pair is immobilized to the hydrogel, and the interacting partner is provided through the buffer compartment, the interaction between the two components can be measured in real time based on the accumulation of mass in the evanescent field and its corresponding effects of the plasmon resonance as measured by the depletion spectrum. This system permits rapid and sensitive real-time measurement of the molecular interactions without the need to label either component.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is a measurement technique that can readily be applied to protein-protein, protein-ligand, or RNA-ligand interactions in order to derive IC₅₀s and Kds of the association reaction between two molecules. In this technique one of the molecules of interest is conjugated with a fluorophore. This is generally the smaller molecule in the system (in this case, the compound of interest). The sample mixture, containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragment thereof, is excited with vertically polarized light. Light is absorbed by the probe fluorophores, and re-emitted a short time later. The degree of polarization of the emitted light is measured. Polarization of the emitted light is dependent on several factors, but most importantly on viscosity of the solution and on the apparent molecular weight of the fluorophore. With proper controls, changes in the degree of polarization of the emitted light depends only on changes in the apparent molecular weight of the fluorophore, which in-turn depends on whether the probe-ligand conjugate is free in solution, or is bound to a receptor. Binding assays based on FP have a number of important advantages, including the measurement of IC₅₀s and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions.

(3) Protein Synthesis. It is contemplated that, in addition to characterization by the foregoing biochemical assays, the compound of interest may also be characterized as a modulator (for example, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays may be performed by administering the compound to a whole organism, tissue, organ, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological and inhibitory properties by determining, for example, its inhibition constant (IC₅₀) for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵S methionine, or similar experiments can be performed to investigate protein synthesis activity. A change in the amount or the rate of protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis. A decrease in the rate or the amount of protein synthesis indicates that the molecule is a inhibitor of protein synthesis.

Furthermore, the compounds may be assayed for anti-proliferative or anti-infective properties on a cellular level. For example, where the target organism is a micro-organism, the activity of compounds of interest may be assayed by growing the micro-organisms of interest in media either containing or lacking the compound. Growth inhibition may be indicative that the molecule may be acting as a protein synthesis inhibitor. More specifically, the activity of the compounds of interest against bacterial pathogens may be demonstrated by the ability of the compound to inhibit growth of defined strains of human pathogens. For this purpose, a panel of bacterial strains can be assembled to include a variety of target pathogenic species, some containing resistance mechanisms that have been characterized. Use of such a panel of organisms permits the determination of structure-activity relationships not only in regards to potency and spectrum, but also with a view to obviating resistance mechanisms. The assays may be performed in microtiter trays according to conventional methodologies as published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines (NCCLS. M7-A5-Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Fifth Edition. NCCLS Document M100-S12/M7 (ISBN 1-56238-394-9).

The compounds may be assayed for anti-inflammatory properties on a cellular level, for example, to determine the inhibition of cytokine production. Further, the compounds may be assessed for calcium flux in CHO cells expressing the human motilin receptor or in animal models for prokinetic behavior such as the rabbit duodenum strip model known to display contractility when a motilin agonist is applied.

5. FORMULATION AND ADMINISTRATION

The compounds of the invention may be useful in the prevention or treatment of a variety of human or other animal disorders, including for example, bacterial infection, fungal infections, viral infections, parasitic diseases, and cancer. It is contemplated that, once identified, the active molecules of the invention may be incorporated into any suitable carrier prior to use. The dose of active molecule, mode of administration and use of suitable carrier will depend upon the intended recipient and target organism. The formulations, both for veterinary and for human medical use, of compounds according to the present invention typically include such compounds in association with a pharmaceutically acceptable carrier.

The carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient. Pharmaceutically acceptable carriers, in this regard, are intended to include any and all solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds (identified or designed according to the invention and/or known in the art) also can be incorporated into the compositions. The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy/microbiology. In general, some formulations are prepared by bringing the compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention should be formulated to be compatible with its intended route of administration. Examples of routes of administration include oral or parenteral, for example, intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, described, for example, in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990). Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration also can be prepared by mixing the drug with a non-irritating excipient such as cocoa butter, other glycerides, or other compositions which are solid at room temperature and liquid at body temperatures. Formulations also can include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes, and the like. Formulations for direct administration can include glycerol and other compositions of high viscosity. Other potentially useful parenteral carriers for these drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Retention enemas also can be used for rectal delivery.

Formulations of the present invention suitable for oral administration may be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the drug; a powder or granular composition; a solution or a suspension in an aqueous liquid or non-aqueous liquid; or an oil-in-water emulsion or a water-in-oil emulsion. The drug may also be administered in the form of a bolus, electuary or paste. A tablet may be made by compressing or moulding the drug optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered drug and suitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients. Oral compositions prepared using a fluid carrier for use as a mouthwash include the compound in the fluid carrier and are applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the drug which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the drug for both intra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. Particularly useful are carriers capable of forming a film or layer over the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface. For example, hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage. Alternatively, tissue-coating solutions, such as pectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling or spray formulations) dispensed with a spray can, a nebulizer, or an atomizer can be used. Such formulations can be in the form of a fine powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations. In the case of self-propelling solution and spray formulations, the effect may be achieved either by choice of a valve having the desired spray characteristics (i.e., being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size. For administration by inhalation, the compounds also can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents and bile salts. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds may be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. Furthermore, administration can be by periodic injections of a bolus, or can be made more continuous by intravenous, intramuscular or intraperitoneal administration from an external reservoir (e.g., an intravenous bag).

Where adhesion to a tissue surface is desired the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The compound then can be painted, sprayed or otherwise applied to the desired tissue surface. Alternatively, the drugs can be formulated for parenteral or oral administration to humans or other mammals, for example, in therapeutically effective amounts, e.g., amounts which provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect.

Where the active compound is to be used as part of a transplant procedure, it can be provided to the living tissue or organ to be transplanted prior to removal of tissue or organ from the donor. The compound can be provided to the donor host. Alternatively or, in addition, once removed from the donor, the organ or living tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly to the desired tissue, as by injection to the tissue, or it can be provided systemically, either by oral or parenteral administration, using any of the methods and formulations described herein and/or known in the art. Where the drug comprises part of a tissue or organ preservation solution, any commercially available preservation solution can be used to advantage. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and lactated Ringer's solution.

The active compound may be administered directly to a tissue locus by applying the compound to a medical device that is placed in contact with the tissue. For example, an active compound may be applied to a stent at the site of vascular injury. Stents can be prepared by any of the methods well known in the pharmaceutical art. See, e.g., Fattori, R. and Piva, T., “Drug-Eluting Stents in Vascular Intervention,” Lancet, 2003, 361, 247-249; Morice, M. C., “A New Era in the Treatment of Coronary Disease?” European Heart Journal, 2003, 24, 209-211; and Toutouzas, K. et al., “Sirolimus-Eluting Stents: A Review of Experimental and Clinical Findings,” Z. Kardiol., 2002, 91(3), 49-57. The stent may be fabricated from stainless steel or another bio-compatible metal, or it may be made of a bio-compatible polymer. The active compound may be linked to the stent surface, embedded and released from polymer materials coated on the stent, or surrounded by and released through a carrier which coats or spans the stent. The stent may be used to administer single or multiple active compounds to tissues adjacent to the stent.

Active compound as identified or designed by the methods described herein can be administered to individuals to treat disorders (prophylactically or therapeutically). In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician may consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of treatment with the drug.

In therapeutic use for treating, or combating, bacterial infections in mammals, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level or tissue level of active component in the animal undergoing treatment which will be anti-microbially effective. The term “effective amount” is understood to mean that the compound of the invention is present in or on the recipient in an amount sufficient to elicit biological activity, for example, anti-microbial activity, anti-fungal activity, anti-viral activity, anti-parasitic activity, anti-proliferative activity, anti-inflammatory activity or ameliorating a symptom of a gastrointestinal motility disorder. Generally, an effective amount of dosage of active component will be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg/kg of body weight/day. The amount administered will also likely depend on such variables as the type and extent of disease or indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the compound delivered, the formulation of the drug, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, for example, 2-4 four times per day.

In light of the foregoing, the specific examples presented below are illustrative only and are not intended to limit the scope of the invention. Other generic and specific configurations will be apparent to those persons skilled in the art.

6. EXAMPLES

Some of the abbreviations used in the following experimental details of the synthesis of the examples are defined below:

hr=hour(s)

min=minute(s)

mol=mole(s)

mmol=millimole(s)

M=molar

μM=micromolar

g=gram(s)

μg=microgram(s)

rt=room temperature

L=liter(s)

mL=milliliter(s)

Et₂O=diethyl ether

THF=tetrahydrofuran

DMSO=dimethyl sulfoxide

EtOAc=ethyl acetate

Et₃N=triethylamine

i-Pr₂NEt=diisopropylethylamine

CH₂Cl₂=methylene chloride

CHCl₃=chloroform

CDCl₃=deuterated chloroform

CCl₄=carbon tetrachloride

MeOH=methanol

CD₃OD=deuterated methanol

EtOH=ethanol

DMF=dimethylformamide

BOC=t-butoxycarbonyl

CBZ=benzyloxycarbonyl

TBS=t-butyldimethylsilyl

TBSCl=t-butyldimethylsilyl chloride

TFA=trifluoroacetic acid

DBU=diazabicycloundecene

TBDPSCl=t-butyldiphenylchlorosilane

Hunig's Base=N,N-diisopropylethylamine

DMAP=4-dimethylaminopyridine

CuI=copper (I) iodide

MsCl=methanesulfonyl chloride

NaN₃=sodium azide

Na₂SO₄=sodium sulfate

NaHCO₃=sodium bicarbonate

NaOH=sodium hydroxide

MgSO₄=magnesium sulfate

K₂CO₃=potassium carbonate

KOH=potassium hydroxide

NH₄OH=ammonium hydroxide

NH₄Cl=ammonium chloride

SiO₂=silica

Pd—C=palladium on carbon

Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)

Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300 spectrometer. Common reaction solvents were either high performance liquid chromatography (HPLC) grade or American Chemical Society (ACS) grade, and anhydrous as obtained from the manufacturer unless otherwise noted. “Chromatography” or “purified by silica gel” refers to flash column chromatography using silica gel (EM Merck, Silica Gel 60, 230-400 mesh) unless otherwise noted.

Example 1 Exemplary Oxazolidinone Derivatives

Exemplary compounds synthesized in accordance with the invention are listed in Table 2. TABLE 2 Compound Number Structure 142

143

144

145

146

147

148

149

150

151

152

153

175

176

177

178

179

180

181

182

183

184

185

186

187

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

Example 2 Synthesis of Compounds 142 and 143

Scheme 28 below depicts the synthesis of compounds 142 and 143 using the chemistries previously exemplified. Briefly, 2-methylamino-ethanol was alkylated with propargyl bromide 154 and tosylate 155 to produce alkynes 156 and 157, respectively. Alkynes 156 and 157 were heated in the presence of the azide intermediate 158 (Brickner, S. J. et al. (1996) J. MED. CHEM 39: 673) to produce compounds 142 and 143, respectively.

Synthesis of Tosylate 155

3-Butyn-1-ol (1.8 g, 25 mmol) was dissolved in methylene chloride (CH₂Cl₂) (40 mL) and triethylamine (Et₃N) (4.18 mL, 30 mmol). The solution was stirred at 0° C. followed by addition of p-toluenesulfonyl chloride (5.05 g, 26.25 mmol). The reaction was allowed to warm to room temperature over a period of 1 hour and stirring was continued overnight. Thin layer chromatography (TLC) analysis (hexanes/ethyl acetate (EtOAc) 6:1) after 20 hours of reaction showed a complete consumption of 3-butyn-1-ol. The precipitated triethylamine hydrochloride was filtered off and the filtrate washed with water (H₂O) (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate (Na₂SO₄) and the solvent evaporated away to give 155 as a light-yellow oil (5.45 g, 97%). The crude oil was used without further purification; however, it could be purified on a silica gel column, first eluting with 8% EtOAc in hexanes followed by 40% EtOAc in hexanes.

Synthesis of Alkyne 157

A suspension of O-tosyl-3-butyn-1-ol (2.8 g, 12.5 mmol), 2-methylaminoethanol (0.93 mL, 11.4 mmol) and sodium bicarbonate (NaHCO₃) was heated at 50° C. for 20 hours. NaHCO₃ was filtered, the solvent was evaporated, and the resulting residue was partitioned between H₂O (30 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was back extracted with EtOAc (4×20 mL). The combined organic layer was dried over Na₂SO₄ and the solvent evaporated away to give an oily residue. The oily crude was purified on silica gel column eluting with 5:1 CH₂Cl₂/methanol (MeOH) to give compound 157 as an oil (0.54 g, 37%).

Synthesis of Alkyne 156

Alkyne 156 was made from 2-methylaminoethanol and propargyl bromide as described for alkyne 157 above.

Synthesis of Triazole 142

Azide 158 (0.15 g, 0.47 mmol) and alkyne 156 (0.212 g, 1.5 mmol) were dissolved in anhydrous tetrahydrofuran (THF) (10 mL) and Hunig's base (2 mL, 11.6 mmol). To this solution was added copper iodide (CuI) (0.136 g, 0.7 mmol) and the resulting suspension stirred at room temperature for 16 hours. TLC (chloroform (CHCl₃)/MeOH 10:1) showed a quantitative consumption of azide 158. Methylene chloride (30 mL) was added, the suspension was filtered and solvent was evaporated from the filtrate. The residue was purified on silica gel eluting with 6-13% MeOH in CH₂Cl₂ to provide triazole 142 (0.11 g, 50.6%). Data for 142: ¹H-NMR (500 MHz, CDCl₃) δ 7.78 (s, 1H), 7.30 (dd, J=15, 3 Hz, 1H), 6.98 (dd, J=9, 2 Hz, 1H), 6.88 (t, J=10 Hz, 1H), 5.08 (m, 1H), 4.77 (m, 2H), 4.15 (t, J=10 Hz, 1H), 3.94 (m, 1H), 3.85 (t, J=5 Hz, 4H), 3.76 (bs, 2H), 3.60 (m, 2H), 3.03 (t, J=4 Hz, 4H), 2.53 (m, 2H), 2.26 (s, 3H).

Synthesis of Triazole 143

Azide 158 (0.383 g, 1.2 mmol) and alkyne 157 (0.24 g, 1.9 mmol) were dissolved in anhydrous THF (12 mL) and Hunig's base (3 mL, 17.4 mmol). To this solution was added CuI (0.43 g, 2.2 mmol) and the resulting suspension was stirred at room temperature for 3 hours. TLC (CH₂Cl₂/MeOH 9:1) showed that the reaction was complete within 3 hours with no further consumption of azide 158 upon stirring overnight. Methylene chloride (50 mL) was added, the suspension was filtered and solvent was evaporated from the filtrate. The residue was purified on silica gel eluting with 10-20% MeOH in CH₂Cl₂ to provide triazole 143 (0.108 g, 20%). Data for 143: ¹H-NMR (500 MHz, CDCl₃/CD₃OD) δ 7.78 (s, 1H), 7.33 (dd, J=15, 3 Hz, 1H), 7.02 (dd, J=9, 2 Hz, 1H), 6.95 (t, J=9 Hz, 1H), 5.10 (m, 1H), 4.76 (m, 2H), 4.19 (t, J=9 Hz, 1H), 3.93 (m, 1H), 3.87 (t, J=5 Hz, 4H), 3.65 (m, 2H), 3.06 (t, J=5 Hz, 4H), 2.90 (t, J=4 Hz, 2H), 2.75 (t, J=5 Hz, 2H), 2.62 (t, J=6 Hz, 2H), 2.34 (s, 3H).

Example 3 Synthesis of Compound 144

Scheme 29 below depicts the synthesis of compound 144 using the chemistries previously exemplified. Cycloaddition of azide 158 and alkyne 159 produced triazole 160. Tosylation of the alcohol of triazole 160, followed by alkylation with 2-methylamino-ethanol, produced 4-substituted triazole 144.

Synthesis of Alcohol 160

Azide 158 (0.15 g, 0.47 mmol) and 4-pentyn-1-ol (0.034 g, 0.39 mmol) were dissolved in anhydrous THF (10 mL) and Hunig's base (2 mL, 11.6 mmol). To this solution was added CuI (0.136 g, 0.7 mmol) and the resulting suspension was stirred at room temperature for 16 hours. TLC(CHCl₃/MeOH 10:1) showed a quantitative consumption of azide 158. Methylene chloride (30 mL) was added, the suspension was filtered and solvent was evaporated from the filtrate. The residue was purified on silica gel eluting with 5-7% MeOH in CH₂Cl₂ to provide 160 (0.077 g, 48.7%).

Synthesis of Triazole 144

Compound 160 (0.072 g, 0.178 mmol) was dissolved in CH₂Cl₂ (2 mL) and Et₃N (0.09 mL, 0.63 mmol). To this solution was added p-toluenesulfonyl chloride (0.0366 g, 0.19 mmol) and stirring continued at room temperature for 20 hours during which a quantitative consumption of compound 160 was noticed by TLC(CH₂Cl₂/MeOH 9:1). The reaction was quenched with 10:1 H₂O/THF within 30 minutes and then partitioned between 10% NaHCO₃ (20 mL) and CH₂Cl₂ (20 mL). The two layers were separated; and the organic layer washed with saturated brine (3×15 mL) and dried over Na₂SO₄. Solvent was evaporated to give an oily residue.

The crude product above was dissolved in THF (3 mL) and Hunig's base (0.31 mL, 1.8 mmol). To this solution was added 2-(methylamino)ethanol (0.037 mL, 0.45 mmol) and stirring was continued at room temperature for 20 hours. The reaction was partitioned between 5% MeOH in CH₂Cl₂ (30 mL) and saturated brine (20 mL). The two layers were separated and the resulting organic layer was washed with saturated brine (2×20 mL), dried over Na₂SO₄ and the solvent was evaporated. The crude product was purified on silica gel eluting with 15-35% MeOH in CH₂Cl₂ to CH₂Cl₂/MeOH/ammonium hydroxide (NH₄OH) 3:1:0.05 to provide compound 144 (0.041 g, 50%). Data for 144: ¹H-NMR (500 MHz, CDCl₃/CD₃OD) δ 7.77 (s, 1H), 7.34 (dd, J=15, 3 Hz, 1H), 7.04 (dd, J=9, 2.5 Hz, 1H), 6.98 (t, J=9 Hz, 1H), 5.12 (m, 1H), 4.77 (m, 2H), 4.20 (t, J=9 Hz, 1H), 3.96 (m, 1H), 3.86 (t, J=5 Hz, 4H), 3.63 (m, 2H), 3.05 (t, J=5 Hz, 4H), 2.71 (t, J=6 Hz, 2H), 2.52 (t, J=6 Hz, 2H), 2.42 (t, J=8 Hz, 2H), 2.26 (s, 3H), 1.83 (m, 2H).

Example 4 Synthesis of Compounds 145-147

Scheme 30 below depicts the synthesis of compounds 145-147 using chemistries previously exemplified. Des-methyl erythromycin amine 39 was alkylated with propargyl bromide 154 or the tosylates 155 and 161 to produce alkynes 162, 163 and 164, respectively. Hydrolysis of alkynes 162, 163 and 164 produces alkynes 165, 166 and 167, respectively, which were then used in a cycloaddition reaction with azide 158 to produce the 4-substituted triazole compounds 145, 146 and 147, respectively.

Synthesis of Tosylate 161

Tosylate 161 was made from 4-pentyn-1-ol using the same protocol described for the synthesis of tosylate 155 above.

Synthesis of Alkyne 165

Alkyne 162 (800 mg) was stirred with 6N hydrochloric acid (HCl) overnight at ambient temperature and heated to 100° C. for 2 hours. The dark solution was cooled to room temperature and extracted with CH₂Cl₂ (3×8 mL) and ethyl ether (Et₂O) (3×8 mL). The aqueous phase was concentrated to obtain a foamy solid, which was redissolved in water (8 mL) and neutralized with NaHCO₃. The solution was extracted with EtOAc (3×10 mL), dried with Na₂SO₄, concentrated and purified by flash chromatography (silica gel, 5% MeOH—CHCl₃) to give the alkyne 165 (85 mg, 40%) as a mixture of anomers.

Synthesis of Alkyne 166 and 167

The same procedure used for the synthesis of alkyne 165 from 162 was used to synthesize alkyne 166 from 163, and alkyne 167 from 164. The alkynes 166 and 167 were used in subsequent chemistry without further purification.

Synthesis of Triazole 145

To a solution of alkyne 165 (80 mg, 0.0402 mmol), azide 158 (155 mg, 0.482 mmol), and Hunig's base (2.1 mL, 12.06 mmol) in THF (5 mL) was added CuI (156 mg, 0.804 mmol) and the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with 10% MeOH—CHCl₃ (50 mL), washed with brine (2×50 mL), dried with Na₂SO₄, and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (silica gel, 10% MeOH—CHCl₃) to give compound 145 (80 mg, 40%). Data for 145: ¹H-NMR (500 MHz, CDCl₃; partial structure) δ 7.72 (s, 1H), 7.28 (d, 1H), 6.95-6.84 (m, 2H, m).

Synthesis of Triazoles 146 and 147

The same procedure used for the synthesis of triazole 145 from 165 was used to synthesize triazole 146 from alkyne 166, and triazole 147 from alkyne 167.

Example 5 Synthesis of Compounds 148-150

Scheme 31 below depicts the synthesis of compounds 148-150 using one exemplary method. Alkynes 162, 163 and 164 were reacted with azide 158 to produce a mixture of the 4-substituted triazoles 148, 149, and 150, respectively.

Scheme 32 below depicts the synthesis of compounds 149 and 150 using an alternative exemplary method. Azide 158 was reacted with tosylates 155 and 161 to produce triazole tosylates 168 and 169, respectively. The reaction of compounds 168 and 169 with amine 39 produced compounds 149 and 150, respectively.

Synthesis of Amine 39

Compound 39 was made from erythromycin A employing the procedure described in U.S. Pat. No. 3,725,385.

Synthesis of Alkyne 163

A mixture of des(N-methyl)erythromycin 39 (1.0 g, 1.4 mmol) and tosylate 155 (1.25 g, 5.6 mmol) in anhydrous THF (15 mL) and Hunig's base (2.2 mL, 11.9 mmol) was kept stirring at 55° C. for 48 hours. The reaction was poured into CH₂Cl₂ (50 mL), extracted with 2% aqueous NH₄OH (3×30 mL) and saturated brine (1×30 mL). The organic layer was dried over Na₂SO₄ and the solvent was evaporated away. The crude was purified on silica gel column eluting with CH₂Cl₂/MeOH 10:1 to give 163 (0.35 g, 32%).

Synthesis of Alkyne 164

Alkyne 164 was made from des(N-methyl)erythromycin 39 and tosylate 161 using the same procedure described for alkyne 163.

Synthesis of Alkyne 162

Alkyne 162 was made from des(N-methyl)erythromycin 39 and propargyl bromide using the same procedure described for alkyne 163.

Synthesis of Tosylate 168

Azide 158 (1.5 g, 4.7 mmol) and tosylate 155 (0.875 g, 3.9 mmol) were dissolved in anhydrous THF (25 mL) and Hunig's base (10 mL, 57.4 mmol). To this solution was added CuI (1.36 g, 7.0 mmol) and the resulting suspension was stirred at room temperature for 2 hours. TLC(CHCl₃/MeOH 10:1) showed a quantitative consumption of azide 158. The reaction was poured into CH₂Cl₂ (60 mL), extracted with saturated NaHCO₃ (3×30 mL) and saturated brine (2×30 mL). The organic layer was dried over Na₂SO₄ and the solvent was evaporated away. The crude was purified on silica gel column eluting with 0-3% MeOH in CH₂Cl₂ to give 168 (1.34 g, 63%).

Synthesis of Triazole 149

Method A: Alkyne 163 (0.80 g, 1.036 mmol) and azide 158 (0.50 g, 1.6 mmol) were dissolved in anhydrous THF (10 mL) and Hunig's base (2.2 mL, 11.6 mmol). To this solution was added CuI (0.403 g, 2.07 mmol) and the resulting suspension stirred at room temperature for 2 hours. CH₂Cl₂ (60 mL) was added, the solution was extracted with saturated NaHCO₃ (3×30 mL), NH₄Cl (3×30 mL) and saturated brine (30 mL). The organic layer was dried over Na₂SO₄ and the solvent was evaporated. The crude was purified on silica gel eluting with CH₂Cl₂/MeOH 15:1 to 10:1 to provide triazole 149 (0.91 g, 80%).

Method B: A mixture of des(N-methyl)erythromycin 39 (0.25 g, 0.342 mmol) and tosylate 168 (0.28 g, 0.51 mmol) in anhydrous THF (5 mL) and Hunig's base (0.65 mL, 3.51 mmol) was stirred at 55° C. for 48 hours. The reaction was poured into CH₂Cl₂ (30 mL), extracted with saturated NaHCO₃ (3×20 mL) and saturated brine (1×20 mL). The organic layer was dried over Na₂SO₄ and the solvent evaporated. The crude product was purified on silica gel column eluting with CH₂Cl₂/MeOH 15:1 to 10:1 to give triazole 149 (0.151 g, 40%). Data for 149: ¹H-NMR, partial, (500 MHz, CDCl₃) δ 7.60 (s, 1H), 7.29 (dd, J=14, 3 Hz, 1H), 6.95 (dd, J=10, 3 Hz, 1H), 6.86 (t, J=9 Hz, 1H), 5.00 (m, 2H), 4.85 (d, J=5H, 1H), 4.67 (m, 2H), 4.37 (d, J=7 Hz, 1H), 4.08 (t, J=10 Hz, 1H), 3.52 (d, J=8 Hz, 1H), 3.44 (m, 1H), 2.66 (m, 2H), 0.82 (t, J=8 Hz, 3H).

Synthesis of Triazole 148

Triazole 148 was made from alkyne 162 and azide 158 using method A as described for triazole 149.

Synthesis of Triazole 150

Triazole 150 was made from alkyne 164 and azide 158 using both methods A and B described for triazole 149. Data for 150: ¹H-NMR, partial, (500 MHz, CDCl₃) δ 7.49 (s, 1H), 7.26 (dd, J=15, 3 Hz, 1H), 6.91 (dd, J=10, 3 Hz, 1H), 6.84 (t, J=9 Hz, 1H), 5.00 (m, 2H), 4.85 (d, J=5H, 1H), 4.67 (m, 2H), 4.38 (d, J=8 Hz, 1H), 4.07 (t, J=10 Hz, 1H), 3.52 (d, J=8 Hz, 1H), 3.44 (m, 1H), 2.69 (m, 2H), 0.78 (t, J=8 Hz, 3H).

Example 6 Synthesis of Compounds 151-153

Scheme 33 below depicts the synthesis of compounds 151-153 using the chemistries previously exemplified. Demethylation of azithromycin 170 selectively produced amine 171. Amine 171 was alkylated with bromide 154 and tosylates 155 and 161 to produce alkynes 172, 173 and 174, respectively. Cycloaddition of alkynes 172, 173 and 174 with azide 158 produced compounds 151, 152 and 153, respectively.

Synthesis of des(N-methyl)azithromycin 171

Azithromycin 170 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was kept at 50° C. followed by addition of iodine (12) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8-9 by adding 1N sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes, however, stirring was continued for 2 hours. TLC(CH₂Cl₂/MeOH/NH₄OH 10:1:0.05) after 2 hours showed a single major product (R_(f)=0.66). The reaction was cooled to room temperature, poured into H₂O (75 mL) containing NH₄OH (1.5 mL) and extracted with CHCl₃ (3×30 mL). The combined organic layer was washed with H₂O (30 mL) containing NH₄OH (1.5 mL), dried over Na₂SO₄ and the solvent evaporated to give a white residue. The crude was purified on silica gel column eluting with CH₂Cl₂/MeOH/NH₄OH 18:1:0.05 to 10:1:0.05 to provide amine 171 (0.41 g, 55%).

Synthesis of Alkyne 172

Alkyne 172 was made from des(N-methyl)azithromycin 171 and propargyl bromide using the same procedure described for the synthesis of compound 163.

Synthesis of Alkyne 173

Alkyne 173 was made from des (N-methyl)azithromycin 171 and tosylate 155 using the same procedure described for the synthesis of compound 163.

Synthesis of Triazole 151

Triazole 151 was made from alkyne 172 and azide 158 using method A as described for the synthesis of compound 149.

Synthesis of Triazole 152

Triazole 152 was made from alkyne 173 and azide 158 using method A as described for the synthesis of compound 149. Data for 152: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.63 (s, 1H), 7.34 (dd, J=14, 2 Hz, 1H), 6.98 (dd, J=9, 2 Hz, 1H), 6.90 (t, J=9 Hz, 1H), 5.11 (d, J=4 Hz, 1H), 4.96 (m, 1H), 4.71 (m, 3H), 4.44 (d, J=7 Hz, 1H), 4.30 (d, J=2 Hz, 1H), 4.10 (m, 2H), 3.86 (m, 5H), 3.04 (m, 5H), 0.90 (t, J=7 Hz, 3H).

Synthesis of Triazole 153

Triazole 153 was made from alkyne 174 and azide 158 using method A as described for compound 149. Data for 153: ¹H-NMR, partial, (500 MHz, CDCl₃) δ 7.50 (s, 1H), 7.29 (dd, J=15, 3 Hz, 1H), 6.94 (dd, J=10, 3 Hz, 1H), 6.87 (t, J=9 Hz, 1H), 5.13 (m, 1H), 5.00 (m, 1H), 4.71 (m, 2H), 4.43 (d, J=7 Hz, 1H), 4.26 (bs, 1H), 3.61 (d, J=8 Hz, 1H), 0.78 (t, J=8 Hz, 3H).

Synthesis of Alkyne 174

Alkyne 174 was made from des(N-methyl)azithromycin 171 and tosylate 161 using the same procedure described for compound 163.

Example 7 Synthesis of Compound 175

Triazole 152 was hydrolyzed with dilute acid to afford the des-cladinose derivative 175.

Synthesis of Triazole 175

Compound 152 (0.120 g, 0.108 mmol) was dissolved in 0.25N HCl (10 mL) and the solution was kept stirring at room temperature for 24 h. The reaction was extracted with CH₂Cl₂ (2×20 mL) and the organic layer was discarded. The aqueous layer was basified with conc. NH₄OH and then extracted with CH₂Cl₂ (3×30 mL). The combined organic layer was extracted with saturated brine (1×20 mL), and dried over Na₂SO₄. TLC(CH₂Cl₂/MeOH/NH₄OH 10:1:0.05) showed >95% conversion to a new lower Rf product (Rf=0.56). The solvent was evaporated to provide 175 as a white solid (0.101 g, 98%). Data for 175: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.58 (s, 1H), 7.26 (dd, J=14, 2 Hz, 1H), 6.91 (dd, J=10, 2 Hz, 1H), 6.82 (t, J=9 Hz, 1H), 4.97 (m, 1H), 4.63-4.66 (m, 3H), 4.36 (d, J=7 Hz, 1H), 4.02 (bs, 1H), 3.78 (t, J=4 Hz, 4H), 2.96 (t, J=5 Hz, 4H), 0.83 (t, J=7 Hz, 3H).

Example 8 Synthesis of Compounds 176-178

Scheme 34 below depicts the synthesis of compounds 176-178 using the chemistries previously exemplified. Azide 188 was treated with alkyne 163 to afford triazole 176. The same azide was used to make triazoles 177 and 178 from alkynes 164 and 173 respectively.

Synthesis of Azide 188

The known azide 188 can be synthesized following the procedure reported in the literature (Gregory, W. A. et al. J. Med. Chem. 1989, 32, 1673).

Synthesis of Triazole 176

This compound was made from alkyne 163 and azide 188 using method A as described for compound 149. Data for 176: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.90 (d, J=9 Hz, 2H), 7.59 (s, 1H), 7.50 (d, J=9 Hz, 2H), 5.01-5.15 (m, 2H), 4.84 (d, J=4 Hz, 1H), 4.71 (m, 2H), 4.36 (d, J=7 Hz, 1H), 4.20 (t, J=7 Hz, 1H) 3.93-4.02 (m, 4H), 3.79 (bs, 1H), 0.79 (t, J=7 Hz, 3H).

Synthesis of Triazole 177

This compound was made from alkyne 164 and azide 188 using method A as described for compound 149. Data for 177: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.98 (d, J=9 Hz, 2H), 7.53-7.56 (m, 3H), 5.07-5.19 (m, 2H), 4.89 (d, J=4 Hz, 1H), 4.75 (m, 2H), 4.43 (d, J=7 Hz, 1H), 4.22 (t, J=7 Hz, 1H), 4.01 (m, 1H), 3.92 (s, 1H), 3.83 (s, 1H), 0.86 (t, J=7 Hz, 3H).

Synthesis of Triazole 178

This compound was made from alkyne 173 and azide 188 using method A as described for compound 149. Data for 178: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.90 (d, J=9 Hz, 2H), 7.55 (s, 1H), 7.48 (d, J=8 Hz, 2H), 4.97-5.02 (m, 2H), 4.61-4.67 (m, 3H), 4.36 (d, J=7 Hz, 1H), 3.95-4.21 (m, 5H), 3.58 (m, 2H), 3.36 (m, 1H), 3.14-3,25 (m, 5H), 0.82 (t, J=7 Hz, 3H).

Example 9 Synthesis of Compounds 179-180

Scheme 35 below depicts the synthesis of compounds 179 and 180 using the chemistries previously exemplified. Azide 189 was treated with alkyne 163 to afford triazole 179. The same azide was used to make triazole 180 from alkyne 173.

Synthesis of Azide 189

The azide was synthesized from 3-fluoroaniline using the chemistry reported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673).

Synthesis of Triazole 179

This compound was made from alkyne 163 and azide 189 using method A as described for compound 149. Data for 179: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.55 (s, 1H), 7.28-7.36 (m, 1H), 7.09 (dd, J=8 Hz, 1.6 Hz, 1H), 6.83 (m, 1H), 5.04-5.12 (m, 2H), 4.88 (d, J=5 Hz, 1H), 4.72 (m, 2H), 4.39 (d, J=7 Hz, 1H), 4.16 (t, J=7 Hz, 1H), 3.82 (s, 1H), 0.83 (t, J=7 Hz, 3H).

Synthesis of Triazole 180

This compound was made from alkyne 173 and azide 189 using method A as described for compound 149. Data for 180: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.55 (s, 1H), 7.22-7.29 (m, 1H), 7.02 (d, J=8 Hz, 1H), 6.77 (m, 1H), 5.01 (m, 2H), 4.63-4.66 (m, 3H), 4.21-4.37 (m, 3H), 3.86 (m, 1H), 3.60 (m, 2H), 3.41 (m, 1H), 0.82 (t, J=8 Hz, 3H).

Example 10 Synthesis of Compound 181

Scheme 36 below depicts the synthesis of compound 181 from azide 194 and alkyne 163. The synthesis of azide 194 began with the conversion of tert-butylamine to benzylcarbamate 190. Carbamate 190 was treated with n-butyllithium and R-glycidyl butyrate to afford alcohol 191. Mesylation to give 192 was followed by cleavage of the t-butyl group with trifluoroacetic acid to provide mesylate 193. Displacement of the mesylate with sodium azide yielded azide 194. The azide was treated with alkyne 163 to afford triazole 181.

Synthesis of Carbamate 190

Sodium bicarbonate (34.48 g., 410.4 mmol) was dissolved in water (680 mL) and tert-butylamine (29 mL, 273.6 mmol) was added. The mixture was cooled to 0° C., and benzyl chloroformate (37 mL) was added. The mixture was stirred 5 min at 0° C., the cold bath removed, and then stirring was continued at room temperature overnight (−16 hours). The mixture was evaporated, and partitioned with a 1:1 mixture of ethyl acetate and water. The organic layer was washed with water, 1N HCl, and then brine. The organic layer was dried with Na₂SO₄, and evaporated to yield 190 (48.45 g., 85% yield) of suitable purity for use in subsequent reactions.

Data for 190: ¹HNMR (300 MHz, CDCl₃): δ 7.37-7.26 (m, 5H), 5.04 (s, 2H), 4.77 (brs, 1H), 1.31 (s, 9H).

Synthesis of Alcohol 191

Carbamate 190 (40 g., 193 mmol) was dissolved in 540 mL tetrahydrofuran, and the solution cooled to −78° C. n-Butyllithium (2.5M in hexane, 85 mL, 212.4 mmol) was added slowly, and the mixture allowed to stir for 45 min at −78° C. R-Glycidyl butyrate (32.6 mL, 212.4 mmol) was added, and the mixture was stirred for 1 h at −78° C. The bath was removed and the reaction allowed to stir overnight at room temperature. The mixture had become thick with solids, and an additional 150 mL of tetrahydrofuran was added, and stirring was continued for another hour. The reaction was quenched with 25 mL saturated ammonium chloride solution, and partitioned with ethyl acetate and water. The aqueous layer was extracted thrice with ethyl acetate, and the combined organic layer was washed with brine, dried (Na₂SO₄), and evaporated to yield 191 (15.21 g., 46% yield) of suitable purity for use in subsequent reactions. Data for 191: ¹HNMR (300 MHz, CDCl₃): δ 4.29 (dd, J=9, 2 Hz, 1H), 4.19 (dd (app), J=8, 8 Hz, 1H), 3.94-3.87 (m, 1H), 3.84-3.76 (m, 1H), 3.71-3.61 (m, 1H), 2.50-2.42 (m, 1H), 1.44 (s, 9H).

Synthesis of Mesylate 192

Alcohol 191 (9.00 g., 52.0 mmol) was dissolved in 215 mL methylene chloride, and the mixture cooled to 0° C. Triethylamine (14.5 mL, 104 mmol) was added, followed by methanesulfonyl chloride (4.43 mL, 57.2 mmol). The mixture was allowed to warm to room temperature and stirred overnight. Methylene chloride (120 mL) was added, and the mixture washed twice with 1N HCl, then twice with 10% aqueous sodium carbonate, and then brine. The organic phase was dried (Na₂SO₄), and evaporated to half its volume. Hexane was added, and the solvents evaporated to form a white precipitate. Before the solution was allowed to evaporate to dryness, more hexane was added and evaporation continued. Again, before the solution was allowed to evaporate to dryness, it was filtered and the solid collected. The precipitate was dried to afford mesylate 192 (11.16 g., 85% yield). Data for 192: ¹HNMR (300 MHz, CDCl₃): δ 4.39-4.34 (m, 1H), 4.25-4.23 (m, 2H), 4.18-4.12 (m, 2H), 3.10 (s, 3H), 1.47 (s, 9H).

Synthesis of Mesylate 193

A solution of mesylate 192 (562 mg, 2.20 mmol) in trifluoroacetic acid (8.0 mL) was heated at 60° C. for 4 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated. The remaining residue was thrice dissolved in chloroform (50 mL) and evaporated to afford mesylate 193 (450 mg, 100% yield) as a tan solid. Data for 193: ¹HNMR (300 MHz, DMSO): δ 7.86 (brs, 1H), 4.34-4.27 (m, 1H), 4.12-4.08 (m, 2H), 4.05-3.98 (m, 2H), 3.14 (s, 3H).

Synthesis of Azide 194

A solution of mesylate 193 (400 mg, 2.10 mmol) in dimethylformamide (4.0 mL) was treated with sodium azide (195 mg, 3.00 mmol) and the mixture heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 194 (105 mg, 35% yield) as a yellow oil of suitable purity for use in subsequent reactions. Data for 194: ¹HNMR (300 MHz, CDCl₃): δ 6.29 (s, 1H), 4.45-4.40 (m, 1H), 4.13-4.07 (m, 1H), 3.97-3.78 (m, 1H), 3.48-3.35 (m, 2H).

Synthesis of Triazole 181

A solution of alkyne 163 (135 mg, 0.180 mmol) in tetrahydrofuran (3.0 mL) was treated with azide 194 (50 mg, 0.350 mmol), i-Pr₂NEt (1.00 mL, 5.30 mmol) and copper (I) iodide (50 mg, 0.270 mmol), and the mixture was stirred under argon at room temperature for 15 h. The reaction mixture was diluted with methylene chloride (100 mL), washed with saturated aqueous NH₄Cl (50 mL), and brine (50 mL). The organic phase was dried (Na₂SO₄), and evaporated. The residue was chromatographed on silica gel using a 5-20% gradient of methanol in 1:1 ethyl acetate/methylene chloride as eluant to provide 80 mg of crude product. The crude was dissolved in methylene chloride (100 mL) and washed with saturated aqueous NH₄Cl (3×100 mL) and dried again. Preparative thin layer chromatography (1:4.5:4.5 methanol/methylene chloride/ethyl acetate as eluant) provided triazole 181 (9.0 mg, 6% yield) as a white film. Data for 181: MS (ESI) m/z 914 (M+H)⁺. ¹HNMR (300 MHz, CDCl₃, partial): δ 7.54 (s, 1H), 6.12 (s, 1H), 5.01-4.95 (m, 1H), 4.79 (d, J=4 Hz, 1H), 4.19-4.11 (m, 2H), 4.08-4.02 (m, 2H), 3.83 (s, 1H), 3.74 (s, 1H)), 3.48-3.30 (m, 4H), 3.23 (s, 3H), 3.09-2.90 (m, 4H), 2.87-2.73 (m, 4H), 2.70-2.50 (m, 2H), 2.28 (s, 3H), 0.80 (t (app), J=7 Hz, 3H).

Example 11 Synthesis of Compounds 182-184

Scheme 37 below depicts the synthesis of compounds 182-184 starting from clarithromycin (195). Clarithromycin is demethylated to afford secondary amine 196 which was subsequently alkylated with tosylate 155 to provide alkyne 197. Alkyne 197 was treated with azides 158, 188, and 189 to yield triazoles 182, 183, and 184 respectively.

Synthesis of Amine 196

To a mixture of clarithromycin (195) (1.00 g, 1.3 mmol) and NaOAc-3H₂O (0.885 g, 6.5 mmol) was added MeOH—H₂O (20 mL, 4:1), and the mixture heated to 55-60° C. Iodine (0.330 g, 1.3 mmol) was added portionwise and the reaction stirred at 55-60° C. for 3 h. The reaction mixture was poured into 50 mL CHCl₃ containing 1 mL ammonium hydroxide. It was extracted with CHCl₃ (4×50 mL), washed with water (70 mL) containing 5 mL ammonium hydroxide, dried (anhydrous Na₂SO₄), concentrated and purified by flash chromatography (silica gel, CHCl₃:MeOH:NH₄OH 100:10:0.1) to afford 196. Yield: 0.9 g (92%).

Synthesis of Alkyne 197

To a solution of N-desmethyl clarithromycin 196 (3.00 g, 4.08 mmol) and tosylate 155 (1.40 g, 6.13 mmol) in THF (45 mL) was added Hunig's base (15 mL) and the mixture was refluxed for 48 h. The reaction mixture was concentrated under reduced pressure and redissolved in CHCl₃ (100 mL). The organic layer was washed with brine (3×100 mL), dried (over Na₂SO₄), and concentrated under reduced pressure. After purification by flash chromatography (silica gel, 5% MeOH in CHCl₃), 2.50 g (78% yield) of pure product 197 was obtained. Data for 197: ¹HNMR (300 MHz, CDCl₃, partial): δ 0.85 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.20 (s, 1H), 3.25 (m, 1H), 3.30 (s, 3H), 3.50 (m, 1H), 3.55 (s, 1H), 3.65 (d, 1H), 3.75 (m, 3H), 4.00 (s, 1H), 4.05 (m, 1H), 4.45 (d, 1H), 4.95 (d, 1H), 5.10 (dd, 1H).

Synthesis of Triazole 182

To a solution of alkyne 197 (0.100 g, 0.127 mmol), azide 158 (0.082 g, 0.254 mmol), and Hunig's Base (0.417 mL) in THF (1.5 mL) was added CuI (0.030 g, 0.16 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with CHCl₃ (50 mL), washed with saturated NH₄Cl (3×50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude reaction mixture was purified on a silica gel column eluting with 3% 2M NH₃-MeOH in CH₂Cl₂ to afford 1, 4 triazole isomer 182 (0.125 g). Data for 182: ¹HNMR (300 MHz, CDCl₃, partial): δ 0.85 (t, 3H), 2.25 (s, 3H), 3.65 (d, 1H), 4.10 (t, 1H), 4.40 (d, 1H), 4.70 (dd, 2H), 4.90 (d, 1H), 5.10-4.95 (m, 2H), 6.88 (t, 1H), 7.00 (dt, 1H), 7.35 (dd, 1H), 7.60 (s, 1H).

Synthesis of Triazole 183

The same protocol used above to synthesize target 182 was used for the cycloaddition of alkyne 197 (0.100 g, 0.127 mmol) and azide 188 (0.066 g, 0.254 mmol) to afford target 183. Data for 183: ¹HNMR (300 MHz, CDCl₃, partial): δ 0.85 (t, 3H), 2.20 (s, 3H), 2.55 (s, 3H), 3.00 (s, 3H), 3.30 (s, 3H), 3.70 (d, 1H), 3.95-4.05 (m, 3H), 4.20 (t, 1H), 4.45 (d, 1H), 4.70 (dd, 2H), 4.90 (d, 1H), 5.10-5.00 (m, 2H), 7.55 (d, 2H), 7.60 (s, 1H), 7.95 (d, 2H).

Synthesis of Triazole 184

Cycloaddition of alkyne 197 (0.050 g, 0.0636 mmol) with azide 189 (0.030 g, 0.127 mmol), using the same procedure for the synthesis of 182, afforded target 184 (0.0253 g). Data for 184: MS (ESI) m/z 1022.3 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 0.86 (t, 1H), 2.25 (s, 3H), 3.00 (s, 3H), 3.30 (s, 3H), 3.50 (m, 1H), 3.65 (s, 1H), 4.10 (t, 1H), 4.40 (d, 1H), 4.70 (dd, 2H), 4.85 (d, 1H), 5.00 (m, 2H), 6.85 (bt, 1H), 7.10 (bd, 1H), 7.35 (bt, 2H), 7.60 (s, 1H).

Example 12 Synthesis of Compound 185

Scheme 38 below depicts the synthesis of compound 185 starting from alkyne 197. Alkyne 197 is hydrolyzed with dilute acid to afford the des-cladinose derivative 198. The hydroxyl on the desosamine sugar of 198 was acetylated to afford alcohol 199 which was then oxidized to ketolide derivative 200. Deacylation of 200 provided alkyne 201, which was then treated with azide 158 to provide triazole 185.

Synthesis of Alcohol 198

To the alkyne 197 (0.700 g) was added 10 mL 0.9N HCl and the mixture was stirred for 4 h at room temperature. The reaction mixture was saturated with sodium chloride and was adjusted to pH 8 using aqueous NH₄OH solution. The solution was extracted with ethyl acetate (3×30 mL), dried (with Na₂SO₄), and concentrated under reduced pressure. Purification of the crude reaction mixture by flash chromatography (silica gel, 60% ethyl acetate in hexane) afforded 0.200 g (35% yield) of the descladinose derivative 198. Data for 198: ¹HNMR (300 MHz, CDCl₃, partial): δ 0.82 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.25 (dd, 1H), 3.55 (m, 2H), 3.70 (s, 1H), 3.85 (s, 1H), 3.95 (s, 1H), 4.40 (d, 1H), 5.15 (dd, 1H).

Synthesis of Acetate 199

To a solution of 198 (0.200 g, 0.32 mmol) in acetone (2 mL) was added acetic anhydride (0.050 mL, 0.5 mmol) and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with saturated sodium bicarbonate (3×50 mL), dried (anhydrous Na₂SO₄), and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 50% ethyl acetate in hexane) to yield 0.100 g (50% yield) of acetate 199. Data for 199: ¹HNMR (300 MHz, CDCl₃, partial): δ 0.84 (t, 3H), 2.00 (s, 3H), 2.20 (s, 3H), 2.90 (s, 3H), 3.00 (q, 1H), 3.25 (s, 1H, 3.47 (m, 2H), 3.70 (bs, 1H), 3.82 (bs, 1H), 3.97 (s, 1H), 4.60 (d, 1H), 4.77 (dd, 1H), 5.15 (dd, 1H).

Synthesis of Ketolide 200

To a solution of acetate 199 (0.090 g, 0.134 mmol), EDC•HCl (0.172 g, 0.90 mmol), and DMSO (0.171 mL, 2.41 mmol) in CH₂Cl₂ (1.5 mL) was added dropwise a solution of pyridinium trifluoroacetate (0.174 g, 0.90 mmol) in CH₂Cl₂ (1 mL) at 15° C. The reaction mixture was slowly warmed up to room temperature and stirred for 3 h. The reaction was quenched with water (2 mL), and allowed to stir for 30 min. The mixture was then poured into CHCl₃ (50 mL), and the organic layer was washed with water (2×50 mL), dried (over anhydrous Na₂SO₄), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to yield 0.070 g (78%) of the ketolide 200. Data for 200: MS (ESI) m/z 668 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 0.86 (t, 3H), 2.00 (s, 3H), 2.24 (s, 3H), 2.70 (s, 3H), 2.95-3.10 (m, 1H), 3.15-3.05 (m, 1H), 3.45-3.65 (m, 1H), 3.80 (q, 1H), 3.90 (s, 1H), 4.28 (d, 1H), 4.40 (d, 1H), 4.76 (dd, 1H), 5.10 (dd, 1H).

Synthesis of Alkyne 201

A solution of ketolide 200 (0.230 g) in MeOH (10 mL) was heated at 50° C. for 48 h. The solvent was removed under reduced pressure to yield pure deacetylated product 201 (0.190 g, 88%). Data for 201: MS (ESI) m/z 626 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 0.85 (t, 3H), 2.25 (s, 3H), 2.70 (s, 3H), 2.97 (q, 1H), 3.10 (t, 1H), 3.18 (dd, 1H), 3.5 (m, 1H), 3.80-3.97 (m, 2H), 4.32 (m, 2H), 5.15 (dd, 1H).

Synthesis of Triazole 185

To a solution of 201 (0.050 g, 0.080 mmol), azide 158 (0.050 g, 0.16 mmol), and Hunig's Base (0.417 mL) in THF (1.5 mL) was added CuI (0.030 g, 0.16 mmol), and the reaction mixture was stirred at room temperature for 2 h. It was diluted with CHCl₃ (50 mL), washed with saturated NH₄Cl (3×50 mL), dried (anhydrous Na₂SO₄) and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 3% 2M NH₃-MeOH in CH₂Cl₂) to afford 185 (0.043 g). Data for 185: MS (ESI) m/z 947.4 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 0.86 (t, 3H), 2.25 (s, 3H), 2.70 (s, 3H), 4.10 (t, 1H), 4.30 (t, 2H), 4.70 (dd, 2H), 5.00 (m, 1H), 5.10 (dd, 1H), 6.90 (t, 1H), 6.95 (dt, 1H), 7.25 (dd, 1H) 7.60 (s, 1H).

Example 13 Synthesis of Compounds 186 and 187

Scheme 39 below depicts the synthesis of compounds 186 and 187. Azide 158 is treated 3-hydroxypropionitrile to yield tetrazole 186. Tetrazole 186 was converted to tosylate 202 which then served to alkylate amine 171 to afford tetrazole 187.

Synthesis of Tetrazole 186

A suspension of azide 158 (0.300 g, 0.940 mmol), 3-hydroxypropionitrile (1.0 mL, 14.2 mmol) and zinc bromide (ZnBr₂) (0.212 g, 0.940 mmol) in 2-propanol/H₂O (4:1) was heated under reflux for 40 h. The reaction was poured into CH₂Cl₂ (50 mL) and H₂O (20 mL) and carefully partitioned (caution: emulsion problem). The aqueous layer was back-extracted with CH₂Cl₂ (3×30 mL). The combined organic layer was dried over Na₂SO₄ and the solvent was evaporated. The crude was purified on silica gel column eluting with 0-10% MeOH in CH₂Cl₂ to provide 186 (0.037 g, 10%). ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.41 (dd, J=14, 3 Hz, 1H), 7.05-7.13 (m, 2H), 6.93 (t, J=9 Hz, 1H), 4.78 (m, 1H), 3.65-4.04 (m, 10H), 3.04 (t, J=5 Hz, 4H), 2.48 (t, J=6 Hz, 2H).

Synthesis of Tosylate 202

Tetrazole 186 (0.028 g, 0.071 mmol) was dissolved in CH₂Cl₂ (2 mL) and Et₃N (0.015 mL, 0.107 mmol). To this solution was added p-toluenesulfonyl chloride (0.034 g, 0.179 mmol) and stirring was continued at room temperature for 24 h during which time a quantitative consumption of 186 was noticed by TLC(CH₂Cl₂/MeOH 9:1, Rf=0.52). The reaction was quenched with H₂O/THF 10:1 within 30 min and then partitioned between 10% NaHCO₃ (15 mL) and CH₂Cl₂ (20 mL). The two layers were separated; the organic layer was washed with saturated brine (3×15 mL) and dried over Na₂SO₄. The solvent was evaporated, and the crude was purified on a silica gel column eluting with 0-3% MeOH in CH₂Cl₂ to provide 202 (0.031 g, 80%).

Synthesis of Tetrazole 187

Compound 187 was made from des(N-methyl)-azithromycin 171 and tosyltetrazole 202 using method B as described for compound 149. Data for 187: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.40 (dd, J=14, 3 Hz, 1H), 6.98 (dd, J=9, 2 Hz, 1H), 6.84 (t, J=9 Hz, 1H), 5.05 (m, 1H), 4.62-4.65 (m, 3H), 4.34 (d, J=7 Hz, 1H), 4.19 (bs, 1H), 3.80 (t, J=5 Hz, 4H), 2.98 (t, J=5 Hz, 4H), 0.82 (t, J=7 Hz, 3H).

Example 14 Synthesis of Compounds 203 and 204

Scheme 40 below depicts the synthesis of compounds 203 and 204. Known azide 253 (see: International Patent Application WO 03/035648) was coupled to 4-hydroxymethylphenylboronic acid to yield biaryl azide 254. Cycloaddition of 254 to alkynes 173 and 197 delivers macrolide targets 203 and 204 respectively.

Synthesis of Biaryl Azide 254

Azide 253 (0.300 g, 0.830 mmol), and 4-hydroxymethylphenylboronic acid (0.152 g, 1.00 mmol) were dissolved in toluene. Potassium carbonate (0.345 g, 2.50 mmol), tetrakis(triphenylphosphine)palladium (0.040 g, 0.035 mmol), ethanol (3 mL) and water (3 mL) were added, and the reaction was degassed thrice before being heated to reflux for two hours. The reaction was allowed to cool to room temperature, and then was partitioned between ethyl acetate (10 mL) and water (10 mL). The layers were separated, and the aqueous phase extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL). The organic layer was dried with MgSO₄, and evaporated. The crude was purified on silica gel column eluting with 20-50% EtOAc in CH₂Cl₂ to provide 254 (0.163 g, 0.476 mmol; 57% yield).

Synthesis of Triazole 203

This compound was obtained from the reaction of alkyne 173 (0.075 g, 0.095 mmol) with azide 254 (0.049 g, 0.143 mmol) in the presence of CuI (0.029 g, 0.143 mmol) in THF (3 mL) and i-Pr₂NEt (0.6 mL) at room temperature within 6 h. The crude reaction was concentrated and then purified on silica gel eluting with CH₂Cl₂/MeOH/NH₄OH 30:1:0.05 to 25:1:0.05 to 20:1:0.05 to 18:1:0.05 to 15:1:0.05 to give 203 as a white solid. Data for 203: MS (ESI) m/z 1129.4 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.65 (s, 1H), 7.53-7.33 (m, 6H), 7.19 (d, J=8 Hz, 1H), 5.03 (m, 2H), 4.70-4.76 (m, 5H), 4.42 (d, J=7 Hz, 1H), 4.28 (d, J=3 Hz, 1H), 4.06 (m, 3H), 3.67 (m, 2H), 3.43 (m, 1H), 0.82 (m, 7H).

Synthesis of Triazole 204

A solution of alkyne 197 (100 mg, 0.127 mmol) in tetrahydrofuran (3.0 mL) was treated with azide 254 (50 mg, 0.15 mmol), i-Pr₂NEt (0.664 mL, 3.81 mmol) and copper (I) iodide (48.4 mg, 0.254 mmol), and the mixture was stirred under argon at room temperature for 15 h. The reaction mixture was diluted with methylene chloride (50 mL), washed with saturated aqueous NH₄Cl (3×50 mL), and brine (2×50 mL). The organic phase was dried (Na₂SO₄), and evaporated. The residue was chromatographed on silica gel using a 4-10% gradient of methanol in chloroform as eluant to provide 69 mg of pure product 204 as a white powder. Data for 204: MS (ESI) m/z 1128.5 (M+H)⁺, 1150.4 (M+Na)⁺. ¹HNMR (300 MHz, CDCl₃, partial): δ 7.72 (s, 1H), 7.52-7.38 (m, 6H), 7.17 (dd, J=8, 2 Hz, 1H) 5.06-5.03 (m, 2H), 4.92 (d, J=4 Hz, 1H), 4.42 (d, J=7 Hz, 1H), 4.18 (t, 1H), 0.82 (t, J=7 Hz, 3H).

Example 15 Synthesis of Compound 205 Scheme 41 depicts the synthesis of compound 205. Available amine 255 was bis-silylated and the amine alkylated to afford diethyl amine derivative 256. The nitro group of 256 was reduced and the resultant amine converted to the benzyl carbamate 257. Conversion of 257 via standard methods to the oxazolidinone 258 was followed by formation of the azides 259 and 260. Azide 260 was treated with alkyne 173 to afford the triazole cycloadduct which was subsequently desilylated to afford compound 205.

Synthesis of Amine 256

To a suspension of amine 255 (2.00 g, 9.33 mmol) in a 1.0 M CH₂Cl₂ solution of TBSCl (22.40 mL, 22.40 mmol) and anhydrous CH₃CN (10 mL) was added DBU (2.96 mL, 19.56 mmol) at 0° C. A clear homogenous solution resulted within a few minutes of the DBU addition and the reaction was stirred at room temperature for 24 h. The reaction was poured into CH₂Cl₂ (60 mL) and extracted with saturated NaHCO₃ (3×30 mL), saturated NH₄Cl (2×30 mL), saturated brine, and then the organic phase was dried over Na₂SO₄. The solvent was evaporated to give a light yellow oil which was used without further purification.

To a solution of the crude product obtained above (2.00 g, 4.54 mmol) in THF (25 mL) and i-Pr₂NEt (10 mL) was added iodoethane (5.00 mL, 61.35 mmol) and the mixture was heated between 70° C. to 75° C. for 48 h. The reaction was worked-up as described in the first step above. The crude was purified on silica gel eluting with hexanes/EtOAc 12:1 to 8:1 to give compound 256 as a light yellow oil (1.16 g, 51%). Data for 256: ¹H-NMR, (300 MHz, CDCl₃): δ 8.08 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 4.99 (d, J=3 Hz, 1H), 3.79 (m, 1H), 3.65 (m, 1H), 2.59 (m, 2H), 2.48 (m, 1H), 2.37 (m, 2H), 0.86 (s, 9H), 0.84 (s, 9H), 0.63 (t, J=7 Hz, 6H), 0.00 (bs, 9H), −0.29 (s, 3H).

Synthesis of Carbamate 257

Compound 256 (1.16 g, 2.34 mmol) was dissolved in absolute EtOH (30 mL) and THF (6 mL). To this solution was added Pd—C (10 wt %, Degussa, 0.11 g) and the reaction was kept under a hydrogen environment using a balloon. TLC after stirring for 48 h revealed a complete consumption of starting material. The reaction was filtered and the filtrate evaporated to give a yellow oil. The crude oil was dissolved in acetone (30 mL) and water (10 mL). The resulting mixture was kept at 0° C. while NaHCO₃ (0.46 g, 5.5 mmol) and CBZCl (0.42 mL, 2.81 mmol) were added. The reaction was allowed to warm up to room temperature and stirred for 4 h. The reaction was poured into CH₂Cl₂ (60 mL) and extracted with saturated NaHCO₃ (3×30 mL), saturated NH₄Cl (2×30 mL), and the organic phase was dried over Na₂SO₄. The solvent was evaporated to give a yellow oil. The crude was purified on silica gel column, eluting with 1-4% MeOH in CH₂Cl₂ to give 257 as a yellow oil (1.02 g, 72%). Data for 257: ¹H-NMR (300 MHz, CDCl₃): δ 7.37-28 (m, 9H), 5.17 (s, 2H), 4.84 (d, J=4 Hz, 1H), 3.77 (m, 1H), 3.60 (m, 1H), 2.69-2.43 (m, 5H), 0.88 (s, 9H), 0.85 (s, 9H), 0.75 (t, J=7 Hz, 6H), 0.00 (bs, 9H), −0.29 (s, 3H).

Synthesis of Alcohol 258

Carbamate 257 (1.02 g, 1.69 mmol) was dissolved in anhydrous THF (10 mL) and the solution was cooled to −78° C. n-Butyllithium (2.5 M in Hexanes) (0.87 mL, 2.18 mmol) was added and the reaction was maintained at −78° C. for 1 h. (R)-Glycidyl butyrate (0.31 mL, 2.184 mmol) was added, the reaction was allowed to warm up to room temperature and stirred for about 16 h. The reaction was partitioned between saturated NH₄Cl (30 mL) and CH₂Cl₂ (50 mL). The organic layer was washed with saturated NH₄Cl (2×30 mL), saturated brine (1×30 mL), and then dried over Na₂SO₄. The solvent was evaporated, and the residue was dissolved in MeOH (20 mL) containing a catalytic amount of sodium methoxide, and the solution was stirred at room temperature for 45 min. The solvent was evaporated, the crude was taken up into CH₂Cl₂ (50 mL) and extracted with saturated NH₄Cl (2×30 mL). The organic phase was dried over Na₂SO₄ and concentrated. The residue was purified on silica gel column, eluting with 5-6% MeOH in CH₂Cl₂ to give 258 as a white foam (0.53 g, 56%). Data for 258: ¹H-NMR (300 MHz, CDCl₃): δ 7.52 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 4.87 (d, J=3 Hz, 1H), 4.70 (m, 1H), 4.02-3.92 (m, 3H), 3.76 (m, 2H), 3.62 (m, 1H), 2.63-2.43 (m, 5H), 0.88 (s, 9H), 0.85 (s, 9H), 0.74 (t, J=7 Hz, 6H), 0.00 (bs, 9H), −0.28 (s, 3H).

Synthesis of Azides 259 and 260

To a solution of oxazolidinone 258 (0.53 g, 0.935 mmol) in anhydrous CH₂Cl₂ (15 mL) and Et₃N (0.28 mL, 2.00 mmol) at 0° C. was added MsCl (0.14 mL, 1.8 mmol). The reaction was stirred at 0° C. for 2 h and the reaction was poured into saturated NaHCO₃ (30 mL) and CH₂Cl₂ (50 mL) and the two layers were separated. The organic layer was extracted with H₂O (2×30 mL), saturated brine (1×30 mL), and dried over Na₂SO₄. The solvent was evaporated to give a yellow oil. The crude was taken up in DMF (10 mL), NaN₃ (0.24 g, 3.74 mmol) was added, and the reaction was heated at 75° C. for 24 h. Water (40 mL) was added and the reaction was extracted with EtOAc (3×40 mL). The combined organic layer was extracted with saturated brine (1×50 mL) and dried over Na₂SO₄. The solvent was evaporated and the crude was purified on a silica gel column, eluting with 1-6% MeOH in CH₂Cl₂ to give azide 259 (0.378 g) and azide 260 (0.027 g). Data for azide 259: ¹H-NMR (300 MHz, CDCl₃): δ 7.54 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 4.87 (d, J=3 Hz, 1H), 4.70 (m, 1H), 4.02-3.92 (m, 3H), 3.77-3.74 (m, 2H), 3.62 (m, 1H), 2.63-2.43 (m, 5H), 0.88 (s, 9H), 0.85 (s, 9H), 0.71 (t, J=7 Hz, 6H), 0.00 (bs, 9H), −0.28 (s, 3H). Data for azide 260: MS (ESI) m/z 478.1 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃): δ 7.59 (d, J=9 Hz, 2H), 7.49 (d, J=9 Hz, 2H), 4.86 (m, 1H), 4.46 (d, J=10 Hz, 1H), 4.20 (t, J=9 Hz, 1H), 3.95 (m, 1H), 3.81-3.61 (m, 4H), 2.98-2.94 (m, 2H), 2.79-2.71 (m, 3H), 1.22 (t, J=7 Hz, 6H), 0.93 (s, 9H), 0.00 (s, 3H), 0.00 (s, 3H).

Synthesis of Compound 205

Alkyne 173 (0.038 g, 0.045 mmol) and azide 260 (0.027 g, 0.057 mmol) were subjected to the cycloaddition reaction in the presence of CuI (0.029 g, 0.143 mmol) in THF (3 mL) and i-Pr₂NEt (0.6 mL) at room temperature for 2 h. The reaction was poured into a mixture containing saturated NH₄Cl/NH₄OH (pH=9.5, 30 mL) and extracted with CH₂Cl₂ (3×30 mL). The combined organic layer was dried over Na₂SO₄ and the solvent evaporated. The crude was purified on silica gel eluting with CH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to give a white solid (0.048 g).

The product obtained above (0.047 g) was dissolved in CH₂Cl₂ (2 mL) and a freshly prepared solution of 1.34 M N,N,N′N′-tetramethylethylenediaamine hydrofluoride (TEMED·HF) in acetonitrile (0.5 mL, 0.67 mmol) was added. Stirring was continued for 3 h and the reaction was concentrated. The crude was purified on a silica gel column, eluting with CHCl₃/MeOH/NH₄OH 15:1:0.05 to give a slightly impure white solid. This was re-purified on a second silica gel column eluting with CH₂Cl₂/MeOH/NH₄OH 18:1:0.04 to 16:1:0.04 to give 205 as a white solid (0.018 g). Data for 205: MS (ESI) m/z 1172.5 (M+Na)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.61 (s, 1H), 7.25-7.17 (m, 4H), 4.89 (m, 2H), 4.58 (m, 3H), 4.17 (d, J=9 Hz, 1H), 4.04 (m, 2H), 3.76 (m, 1H), 3.46-3.31 (m, 4H), 2.85 (d, J=9 Hz, 1H), 0.75 (m, 7H).

Example 16 Synthesis of Compounds 206 and 207

Scheme 42 depicts the synthesis of targets 206 and 207. The aromatic substitution reaction of 3,4-difluoronitrobenzene and 2-(methylamino)ethanol provided nitroaniline 261. The alcohol of 261 was protected and the nitro group was reduced to afford amine 262. Conversion of 262 to carbamate 263 was followed by synthesis of the oxazolidinone 264. Alcohol 264 was converted to azides 265 and 266, and the latter was acylated to afford azide 267. The cycloaddition of 266 and 267 with alkyne 173 afforded targets 206 and 207 respectively.

Synthesis of Amine 261

To a solution of 3,4-difluoronitrobenzene (2.4 mL, 29.72 mmol) in EtOAc (20 mL) and i-Pr₂NEt (5.1 mL, 29.30 mmol) was slowly added 2-(methylamino)ethanol (3 mL, 27.10 mmol) at 0° C. The reaction was allowed to warm up to room temperature and stirring was continued overnight. The reaction was poured into EtOAc (30 mL) and extracted with H₂O (50 mL). The aqueous layer was basified with KOH pellets (pH 10.0) and extracted with CH₂Cl₂ (3×30 mL). The combined organic layer was dried over Na₂SO₄ and the solvent evaporated to give a yellow solid residue. The crude was dissolved in 6 N HCl (60 mL) at 0° C., extracted with CH₂Cl₂ (3×30 mL), and the organic layer was back extracted with 6 N HCl (25 mL). The combined acid layer was basified with KOH pellets at 0° C. and extracted with CH₂Cl₂ (4×40 mL). The organic phase was dried over Na₂SO₄ and the solvent evaporated to give 261 as a yellow solid (Rf=0.56, CH₂Cl₂/MeOH, 4.59 g, 79%). Data for 261: MS (ESI) m/z 214.7 (M+H)⁺.

Synthesis of Amine 262

Compound 261 (4.5 g, 21 mmol), imidazole (2.91 g, 42 mmol) and DMAP (0.26 g, 2.1 mmol) were dissolved in anhydrous CH₂Cl₂ (50 mL). To this solution was added TBSCl (3.33 g, 22.10 mmol) and stirring was continued for 2 h. CH₂Cl₂ (30 mL) was added and the mixture was extracted with saturated NaHCO₃ (2×50 mL) and saturated brine (lx 50 mL). The organic phase was dried over Na₂SO₄ and evaporated to give a yellow oil. The oil was dissolved in absolute EtOH (50 mL) and THF (10 mL). To this solution was added Pd—C (10 wt %, Degussa, 0.50 g) and the reaction was kept under a hydrogen environment using a balloon. TLC after stirring for 24 h revealed a complete consumption of starting material. The reaction was filtered and the filtrate evaporated to give 262 as a red oil which was used in further reactions without further purification. Data for 262: MS (ESI) m/z 298.7 (M+H)⁺.

Synthesis of Oxazolidinone 264

Crude oil 262 was dissolved in acetone (60 mL) and water (20 mL). The resulting mixture was kept at 0° C., and NaHCO₃ (4.13 g, 49.40 mmol) and CBZCl (3.77 mL, 25.22 mmol) were added. The reaction was allowed to warm up to room temperature and stirring continued for 2 h. The reaction was poured into CH₂Cl₂ (120 mL) and extracted with saturated NaHCO₃ (2×50 mL) and saturated brine (1×50 mL). The organic phase was dried over Na₂SO₄ and evaporated to give carbamate 263 as a red oily residue.

The crude 263 above was dissolved in anhydrous THF (50 mL) and the solution was cooled to −78° C. n-Butyllithium (2.5 M in Hexanes) (10.8 mL, 27 mmol) was added and the reaction was maintained at −78° C. for 1 h. (R)-Glycidyl butyrate (3.83 mL, 27 mmol) was added, the reaction was allowed to warm up to room temperature, and stirring was continued for about 16 h. The reaction was poured into EtOAc (100 mL), extracted with saturated NaHCO₃ (2×60 mL) and saturated brine (1×60 mL). The organic phase was dried over Na₂SO₄ and evaporated. The residue was dissolved in MeOH (50 mL) containing sodium methoxide (25% wt/vol in MeOH, 0.3 mL) and the solution was stirred at room temperature for 30 min. The solvent was evaporated, and the crude was poured into EtOAc (100 mL), and washed with saturated NaHCO₃ (1×60 mL) and saturated brine (1×60 mL). The organic phase was dried over Na₂SO₄ and evaporated to give a brown oily residue. The residue was purified on a silica gel column, eluting with CH₂Cl₂/MeOH 25:1 to 20:1 to give 264 as a brown solid (5.93 g, 71%). Data for 264: MS (ESI) m/z 399.0 (M+H)⁺.

Synthesis of Azides 265 and 266

To a solution of oxazolidinone 264 (3.00 g, 7.54 mmol) in anhydrous CH₂Cl₂ (40 mL) and Et₃N (2.16 mL, 15.45 mmol) at 0° C. was added MsCl (1.03 mL, 13.20 mmol). The reaction was stirred at 0° C. for 2 h and then was poured into saturated NaHCO₃ (60 mL) and CH₂Cl₂ (100 mL) and the two layers separated. The organic layer was extracted with H₂O (2×40 mL), saturated brine (1×40 mL) and dried over Na₂SO₄. The solvent was evaporated to give a brown oil. The crude was taken up in DMF (25 mL), then NaN₃ (2.00 g, 30.16 mmol) was added and the reaction was kept at 70° C. for 18 h. Water (60 mL) and EtOAc (100 mL) were added and the two layers separated. The aqueous layer was extracted with EtOAc (2×50 mL), and the combined organic layer was dried over Na₂SO₄ and evaporated. The crude was purified on a silica gel column, eluting with CH₂Cl₂/MeOH 30:1 to 24:1 to 20:1 to give azide 265 (2.16 g, 68%, white solid) and azide 266 (0.33 g, 14%, brown foam). Data for azide 265: MS (ESI) m/z 424.0 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃): δ 7.35 (dd, J=15, 3 Hz, 1H), 7.06 (dd, J=9, 2 Hz, 1H), 6.88 (m, 1H), 4.75 (m, 1H), 4.02 (t, J=9 Hz, 1H), 3.81-3.74 (m, 3H), 3.67 (dd, J=13, 5 Hz, 1H), 3.57 (dd, J=13, 4 Hz, 1H), 3.28 (t, J=6 Hz, 2H), 2.90 (s, 3H), 0.85 (s, 9H), 0.01 (s, 6H). Data for azide 266: MS (ESI) m/z 309.8 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃): δ 7.37 (dd, J=15, 3 Hz, 1H), 7.06 (dd, J=9, 3 Hz, 1H), 6.94 (t, J=6 Hz, 1H), 4.77 (m, 1H), 4.03 (t, J=9 Hz, 1H), 3.80-3.56 (m, 5H), 3.20 (t, J=6 Hz, 2H), 2.81 (s, 3H).

Synthesis of Azide 267

To a solution of azide 266 (0.16 g, 0.52 mmol) in THF (5 mL) and Et₃N (0.10 mL, 0.68 mmol) was added Ac₂O (0.065 mL, 0.68 mmol) and a few grains of DMAP at room temperature. Stirring was continued for 3 h, then the reaction was quenched with aqueous MeOH, poured into NaHCO₃ (30 mL), and extracted with CH₂Cl₂ (50 mL). The CH₂Cl₂ layer was extracted once with saturated brine (30 mL) and dried over Na₂SO₄. The solvent was evaporated to give 267 as a brown oil (0.182 g, 99%). MS (ESI) m/z 351.9 (M+H)⁺.

Synthesis of Triazole 206

This compound was obtained from the reaction of alkyne 173 (0.315 g, 0.40 mmol) with azide 266 (0.16 g, 0.52 mmol) in the presence of CuI (0.057 g, 0.30 mmol) in THF (10 mL) and i-Pr₂NEt (0.1 mL) at room temperature within 30 min under argon. Saturated NH₄Cl (30 mL) was added, and stirring was continued for 5 min. The reaction was basified with NH₄OH to pH 9.0. CH₂Cl₂ (40 mL) was added, the two layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (2×25 mL). The combined organic layer was dried over Na₂SO₄ and the solvent evaporated. The crude was purified on silica gel eluting with CH₂Cl₂/MeOH/NH₄OH 18:1:0.05 to 15:1:0.05 to 12:1:0.05 to give 206 as a white solid (0.426 g, 97%). Data for 206: MS (ESI) m/z 1096.4 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.61 (s, 1H), 7.24 (dd, J=15, 2 Hz, 1H), 6.90 (m, 2H), 5.00 (m, 2H), 4.69 (m, 3H), 4.43 (d, J=7 Hz, 1H), 4.24 (m, 2H), 3.88 (m, 1H), 3.74 (t, J=5 Hz, 2H), 0.88 (m, 7H).

Synthesis of Triazole 207

This compound was obtained from the reaction of alkyne 173 (0.315 g, 0.40 mmol) with azide 267 (0.182 g, 0.52 mmol) as described for triazole 206 above. The crude was purified on silica gel, first eluting with CH₂Cl₂/MeOH 18:1 to remove unreacted 267, then with CH₂Cl₂/MeOH 15:1 to 12:1 to 10:1 containing a trace amount of NH₄OH to give 207 as a white solid (0.42 g, 92%). Data for 207: MS (ESI) m/z 1138.3 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.62 (s, 1H), 7.29 (dd, J=15, 2 Hz, 1H), 6.93 (m, 1H), 6.85 (t, J=9 Hz, 1H), 5.01 (m, 2H), 4.66 (m, 3H), 4.22 (t, J=6 Hz, 2H), 3.89 (m, 1H), 3.38 (t, J=6 Hz, 2H), 0.89 (m, 7H).

Example 17 Synthesis of Triazole 208

Scheme 43 depicts the synthesis of triazole 208. Azide 188 was converted to benzylic alcohol 268, which was subsequently converted to triazole 208 using the copper-catalyzed cycloaddition chemistry described above.

Synthesis of Azide 268

A solution of azide 188 (0.38 g, 1.43 mmol) in anhydrous THF (5 mL) was cooled to −78° C. To this solution was slowly added 1 M methyl magnesiumbromide (CH₃MgBr) in butyl ether (1.5 mL, 1.50 mmol) within 20 min. The reaction was allowed to warm up to room temperature and stirring was continued for 3 h. The reaction was quenched with H₂O (20 mL) and extracted with CH₂Cl₂ (40 mL). The organic layer was extracted with saturated brine (25 mL), dried over Na₂SO₄ and the solvent evaporated. The crude was purified on silica gel eluting with EtOAc/Hexanes 3:1 to 5:1 to give azide 268 as a white foam (0.178 g, 45%). Data for 268: MS (ESI) m/z 276.8 (M+H)⁺.

Synthesis of Triazole 208

This compound was obtained from the reaction of alkyne 173 (0.20 g, 0.25 mmol) with azide 268 (0.095 g, 0.34 mmol) as described for triazole 206 above except that the reaction was first quenched with saturated NH₄Cl/NH₄OH 5:1 (pH=9.5, 30 mL) before the usual CH₂Cl₂ extraction. The crude was purified on silica gel, first eluting with CH₂Cl₂/MeOH 12:1, then with CH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 12:1:0.05 to give 208 as a white solid (0.056 g). Data for 208: MS (ESI) m/z 1063.4 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.63 (s, 1H), 7.48 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H), 5.03 (m, 2H), 4.72 (m, 3H), 4.44 (d, J=7 Hz, 1H), 4.30 (d, J=5 Hz, 1H), 4.16 (t, J=9 Hz, 1H), 3.92 (m, 1H), 3.67 (m, 2H), 0.90 (m, 7H).

Example 18 Synthesis of Triazole 209

Scheme 44 shows the synthesis of triazole 209. 3-Aminopyridine was converted to carbamate 269 which was subsequently transformed to azide 271 using chemistry similar to that reported above. Cycloaddition of 271 with alkyne 173 yielded triazole 209.

Synthesis of Alcohol 270

Oxazolidinone 270 was synthesized from 3-aminopyridine using the chemistry reported for the conversion of amine 262 to alcohol 264 (Example 16). The crude was purified on silica gel column, eluting with CH₂Cl₂/MeOH 19:1 to give 270 as a white solid (46%). Data for 270: MS (ESI) m/z 194.7 (M+H)⁺.

Synthesis of Azide 271

Azide 271 was synthesized from alcohol 270 as described for the synthesis of azides 259 and 260 (Example 15) except that the sodium azide reaction with the intermediate mesylated derivative of 270 was complete within 2 h. The reaction was worked-up with saturated NaHCO₃ (30 mL) and EtOAc (4×40 mL). The organic phase was dried over Na₂SO₄ and evaporated. The crude was purified on silica gel, eluting with CH₂Cl₂/MeOH 17:1 to give 271 as a colorless, thick oil (81%). Data for 271: MS (ESI) m/z 220.0 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃): δ 8.60 (d, J=2 Hz, 1H), 8.35 (dd, J=5, 1 Hz, 1H), 8.07 (m, 1H), 7.28 (dd, J=8, 5 Hz, 1H), 4.83 (m, 1H), 4.11 (t, J=9 Hz, 1H), 3.87 (dd, J=9, 6 Hz, 1H), 3.72 (dd, J=14, 4 Hz, 1H), 3.57 (dd, J=14, 5 Hz, 1H).

Synthesis of Triazole 209

This compound was obtained from the reaction of alkyne 173 (0.17 g, 0.22 mmol) with azide 271 (0.080 g, 0.36 mmol) as described for triazole 206 above (Example 16) except that the reaction was allowed to stir for 12 h. The crude was purified on silica gel, first eluting with CH₂Cl₂/MeOH 17:1, then with CH₂Cl₂/MeOH/NH₄OH 17:1:0.05 to 15:1:0.05 to 12:1:0.05 to 10:1:0.05 to give 209 as a white solid (0.117 g, 54%). Data for 209: MS (ESI) m/z 1006.5 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 8.67 (d, J=3 Hz, 1H), 8.36 (dd, J=5, 1 Hz, 1H), 7.84 (m, 1H), 7.62 (s, 1H), 7.28 (m, 1H), 5.16-5.05 (m, 2H), 4.75 (d, J=4 Hz, 2H), 4.45 (d, J=7 Hz, 1H), 3.64 (t, J=7 Hz, 1H), 0.88 (m, 7H).

Example 19 Synthesis of Triazole 210

Triazole 210 was synthesized by dealkylation of compound 149 (Scheme 45).

Synthesis of Triazole 210

Compound 149 (0.20 g, 0.183 mmol) and NaOAc (0.15 g, 1.83 mmol) were dissolved in 80% aqueous MeOH (5 mL), and the mixture was heated under gentle reflux for 1 h. The reaction was allowed to cool to room temperature and H₂O/NH₄OH 8:1 (9 mL) was added. The mixture was extracted with CH₂Cl₂ (3×20 mL), the combined organic layer was extracted with H₂O/NH₄OH 5:1 (20 mL), dried over Na₂SO₄ and the solvent evaporated. The crude was purified on silica gel eluting with CH₂Cl₂/MeOH/H₂O (containing a trace of NH₄OH) 20:1:0.05 to 18:1:0.05 to 15:1:0.05 to 12:1:0.05 to give 210 as a white solid (0.049 g). Data for 210: MS (ESI) m/z 1079.4 (M+Na)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.55 (s, 1H), 7.25 (dd, J=14, 2 Hz, 1H), 6.91 (dd, J=9, 2 Hz, 1H), 6.82 (t, J=9 Hz, 1H), 4.96 (m, 2H), 4.81 (d, J=4 Hz, 1H), 4.64 (m, 2H), 4.31 (d, J=7 Hz, 1H), 4.05 (t, J=9 Hz, 1H), 3.47 (d, J=7 Hz, 2H), 2.29-2.25 (m, 2H), 0.78 (t, J=7 Hz, 3H).

Example 20 Synthesis of Triazole 211

A solution of alkyne 198 (136 mg, 0.216 mmol) in tetrahydrofuran (3.0 mL) was treated with azide 158 (104 mg, 0.325 mmol), i-Pr₂NEt (1.1 mL, 6.58 mmol) and copper (I) iodide (82 mg, 0.432 mmol), and the mixture was stirred under argon at room temperature for 15 h. The reaction mixture was diluted with methylene chloride (50 mL), washed with saturated aqueous NH₄Cl (3×50 mL), and brine (2×50 mL). The organic phase was dried (Na₂SO₄), and evaporated. The residue was chromatographed on silica gel using a 4-10% gradient of methanol in methylene chloride as eluant to provide 211 as a white solid (0.112 g, 0.118 mmol, 56%). Data for 211: MS (ESI) m/z 949.3 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.68 (s, 1H), 7.33 (dd, J=2, 14 Hz, 1H), 6.97 (dd, J=2, 9 Hz, 1H), 6.89 (t, J=9 Hz, 1H), 5.16 (dd, J=3, 11 Hz, 1H), 5.09-4.99 (m, 1H), 4.72 (ddd, J=4, 15, 18 Hz, 2H), 4.36 (d, J=7 Hz, 1H), 4.13 (t, J=9 Hz, 2H), 0.83 (t, J=7 Hz, 3H).

Example 21 Synthesis of Triazole 212

To a mixture of alkyne 201 (48 mg, 0.076 mmol), azide 189 (19.9 mg, 0.084 mmol) and copper (I) iodide (8 mg, 0.038 mmol) was added THF (3 mL) and the mixture was repeatedly degassed and flushed with argon. Then i-Pr₂NEt (0.1 mL) was introduced and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into NH₄Cl (30 mL) and stirred for few minutes. Then NH₄OH (3 mL) was added and the mixture was extracted with methylene chloride (3×40 ml). The combined organic layers were dried (Na₂SO₄), concentrated and flash chromatographed over silica gel (methylene chloride: MeOH:NH₄OH=48:2:0.05) to provide 212 (55 mg, 0.06 mmol, 79%). Data for 212: MS (ESI) m/z 862.3 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.60 (s, 1H), 7.32 (m, 1H), 7.09 (dd, J=3, 9 Hz, 1H), 6.85 (brt, 1H), 0.86 (t, J=7 Hz, 3H).

Example 22 Synthesis of Triazole 213

Scheme 46 illustrates the synthesis of triazole 213. 3,4-Difluoronitrobenzene is converted to nitroaniline 272 via an aromatic substitution reaction. The nitro group of 272 is reduced to afford aniline 273 which is transformed to carbamate 274. Oxazolidinone formation to provide 275 is followed by conversion to the azide to yield 277. Cycloaddition of azide 277 with alkyne 173 afforded triazole 213.

Synthesis of Nitroaniline 272

3,4-Difluoronitrobenzene (3 mL, 27.1 mmol) was added to a solution of dimethyl amine (15 mL, 29.8 mmol) and i-Pr₂NEt (5.2 ml, 29.8 mmol) in ethyl acetate (20 mL) at 0° C. and the mixture was stirred at room temperature overnight. The yellow solution was concentrated and redissolved in methylene chloride (100 mL) and then washed with water (50 mL). The aqueous layer was basified with KOH pellets and back extracted with methylene chloride (2×50 mL). The combined organic layer after evaporation afforded a yellow solid which was dissolved in 6N HCl (60 mL) at 0° C. and washed with methylene chloride (3×60 mL). The solution was basified with KOH pellets (pH 10) and extracted with methylene chloride (3×100 mL). The combined organic phase was dried (Na₂SO₄) and concentrated to provide 272 (1.8 g). Data for 272: ¹HNMR (300 MHz, CDCl₃): δ 7.95 (dd, J=2, 8 Hz, 1H), 7.88 (dd, J=3, 14 Hz, 1H), 6.72 (t, J=9 Hz, 1H), 3.10 (s, 6H).

Synthesis of Aniline 273

To a solution of nitroaniline 272 (1.7 g, 9.2 mmol) in EtOH and THF (2:1, 30 mL) was added 10% Pd—C (0.2 g) and the mixture was stirred overnight at room temperature under hydrogen atmosphere. It was filtered through a Whatman filter paper and the residue was washed with methylene chloride (4×25 mL). The combined organic layer was evaporated to provide 273 (1.3 g). Data for 273: ¹HNMR (300 MHz, CDCl₃): δ 6.81 (t, J=11 Hz, 1H), 6.46-6.37 (m, 2H), 2.73 (s, 6H).

Synthesis of Carbamate 274

To a solution of aniline 273 (1.3 g, 8.4 mmol) in a mixture of acetone (20 mL) and water (5 mL) was added NaHCO₃ (1.76 g, 21 mmol) at 0° C. and the mixture was stirred for few minutes. Then benzyl chloroformate (1.5 mL, 10.1 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated and dissolved in methylene chloride (50 mL). The organic layer was washed with brine (3×50 mL), dried (Na₂SO₄) and concentrated to provide 274 (2.4 g) of suitable purity for use in subsequent reactions. Data for 274: ¹HNMR (300 MHz, CDCl₃): δ 7.38-7.12 (m, 6H), 6.95 (brd, J=8 Hz, 1H), 6.84 (t, J=9 Hz, 1H), 6.57 (brs, 1H), 5.18 (s, 2H), 2.78 (s, 6H).

Synthesis of Oxazolidinone 275

To a solution of carbamate 274 (2.4 g, 8.3 mmol) in THF (80 mL) was added n-BuLi (4.32 mL, 2.5 M in hexane, 10.79 mmol) at −78° C. and the mixture was stirred for 1 h. (R)-Glycidyl butyrate (1.5 mL, 10.87 mmol) was added and the reaction warmed to room temperature and allowed to stir overnight. The reaction was carefully poured into saturated NH₄Cl (70 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×200 mL), dried (Na₂SO₄) and concentrated. Flash chromatography over silica gel (60%-100% EtOAc in hexanes) provided 275 (2 g) 275 as a white solid. Data for 275: ¹HNMR (300 MHz, CDCl₃): δ 7.38 (dd, J=3, 15 Hz, 1H), 7.10 (dd, J=3, 9 Hz 1H), 6.88 (t, J=12 Hz, 1H), 4.75-4.71 (m, 1H), 4.02-3.93 (m, 3H), 3.79-3.75 (m, 1H), 2.81 (s, 6H).

Synthesis of Azide 277

To alcohol 275 (900 mg, 3.54 mmol) in methylene chloride (35 mL) at 0° C. was added triethylamine (0.5 mL, 3.58 mmol) and methanesulfonyl chloride (0.41 mL, 5.31 mmol). After stirring for 1 h at 0° C., the reaction was poured into water (100 mL) and extracted with methylene chloride (3×100 mL). The combined organic layers were washed with water (2×100 mL), dried (Na₂SO₄) and concentrated to yield 1.1 g of pure product 276. To a solution of mesylate 276 (1.1 g, 3.3 mmol) in DMF (15 mL) was added sodium azide (646 mg, 9.9 mmol) and the reaction was heated at 75° C. overnight. The reaction was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×100 mL), dried (Na₂SO₄) and concentrated to provide a solid. The material was further purified by flash chromatography over silica gel (50% EtOAc in hexanes) to yield 858 mg of pure azide 277. Data for 277: ¹HNMR (300 MHz, CDCl₃): δ 7.38 (dd, J=3, 15 Hz, 1H), 7.10 (dd, J=3, 9 Hz 1H), 6.89 (t, J=9 Hz, 1H), 4.78-4.75 (m, 1H), 4.01 (t, J=9 Hz, 1H), 3.81 (dd, J=6, 9 Hz, 1H), 3.69 (dd, J=5, 13 Hz, 1H), 3.58 (dd, J=5, 13 Hz, 1H), 2.82 (s, 3H).

Synthesis of Triazole 213

To a mixture of alkyne 173 (200 mg, 0.254 mmol), azide 277 (85 mg, 0.305 mmol) and copper (I) iodide (24 mg, 0.127 mmol) was added THF (10 mL) and the mixture was repeatedly degassed and flushed with argon. Then i-Pr₂NEt (0.1 mL) was introduced and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into NH₄Cl (30 mL) and stirred for few minutes. Then NH₄OH (3 mL) was added and the mixture extracted with methylene chloride (3×40 ml). The combined organic layers were dried (Na₂SO₄), concentrated and flash chromatographed over silica gel (methylene chloride: MeOH:NH₄OH=12:1; 0.05) to provide 223 mg of triazole 213. Data for 213: MS (ESI) m/z 1066.5 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.63 (s, 1H), 7.27 (dd, J=2, 8 Hz, 1H), 6.94 (dd, J=2, 9 Hz, 1H), 6.84 (t, J=9 Hz, 1H), 5.30-5.04 (m, 2H), 0.89 (t, J=7 Hz, 3H).

Example 23 Synthesis of Isoxazole 214

Scheme 47 exemplifies the synthesis of isoxazole 214. Known alkyne 278 (Zacharie, B. et al. J. Med. Chem. 1997, 40, 2883) was converted by hydroxylamine to hydroxyisoxazole 279. The Mitsunobu reaction of 279 with alcohol 280 (synthesized from 3-fluoroaniline using the chemistry reported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673)) afforded isoxazole 281. Desilylation of 281 afforded alcohol 282 which was subsequently converted to tosylate 283. Alkylation of amine 171 with tosylate 283 yielded isoxazole 214.

Synthesis of Hydroxyisoxazole 279

To a solution of hydroxylamine hydrochloride (208 mg, 3.0 mmol) in MeOH (5 mL) was added 10% NaOH (3.14 mL, 7.85 mmol) solution followed by a solution of alkyne 278 (900 mg, 2.5 mmol) in MeOH (1.5 mL). The mixture was stirred overnight at room temperature and was then acidified with 6N HCl (pH 2), saturated with sodium sulphate. The mixture was extracted with diethyl ether (3×50 mL). The combined organic layers were washed with water (3×100 mL), dried (Na₂SO₄), concentrated and chromatographed over silica gel (20% EtOAc in hexanes) to provide 280 mg pure isoxazole 279 as a white solid. Data for 279: MS (ESI) m/z 408.9 (M+CH₃CN)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.62 (brd, 4H), 7.46-7.35 (m, 6H), 5.76 (s, 1H), 3.91 (t, J=6 Hz, 2H), 2.86 (t, J=7 Hz, 2H), 1.03 (s, 9H).

Synthesis of Isoxazole 281

To a solution of isoxazole 279 (100 mg, 0.272 mmol), alcohol 280 (86 mg, 0.408 mmol) and triphenyl phosphine (114 mg, 0.435 mmol) in THF (8 mL) was added diisopropyl azodicarboxylate (0.08 mL, 0.408 mmol) at −20° C. The solution was warmed to room temperature and stirred for 3 h. The mixture was concentrated and chromatographed over silica gel (25-30% EtOAc in hexanes) to provide 140 mg of 281. Data for 281: MS (ESI) m/z 583.0 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.61 (dd, J=3, 9 Hz, 4H), 7.48-7.32 (m, 9H), 6.85 (brt, 1H), 5.72 (s, 1H), 5.02-4.94 (m, 1H), 4.53 (dd, J=4, 12 Hz, 1H), 4.46 (dd, J=5, 12 Hz, 1H), 4.16-4.09 (m, 2H), 3.93 (t, J=6 Hz, 2H), 2.87 (t, J=6 Hz, 2H), 1.03 (s, 9H).

Synthesis of Isoxazole 282

To a solution of silyl ether 281 (140 mg, 0.25 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (0.5 mL, 1M in THF) at 0° C. and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and dissolved in EtOAc (50 mL). The organic layer was washed with brine (2×50 mL), dried (Na₂SO₄), concentrated and chromatographed over silica gel (70% EtOAc in hexanes) to provide 70 mg of 282. Data for 282: MS (ESI) m/z 322.8 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.45 (ddd, J=2, 5, 11 Hz, 1H), 7.30-7.21 (m, 2H), 6.88-6.82 (m, 1H), 5.78 (s, 1H), 5.04-4.96 (m, 1H), 4.52 (dd, J=4, 12 Hz, 1H), 4.43 (dd, J=5, 11 Hz, 1H), 4.15 (t, J=9 Hz, 1H), 3.96 (dd, J=6, 9 Hz, 1H), 3.91 (t, J=6 Hz, 2H), 2.91 (t, J=6 Hz).

Synthesis of Tosylate 283

p-Toluenesulfonyl chloride (71.5 mg, 0.375 mmol) was added to a solution of isoxazole

282 (60 mg, 0.187 mmol), triethylamine (0.065 mL, 0.468 mmol) and DMAP (cat.) in methylene chloride (5 mL) at 0° C. The mixture was then allowed to stir at room temperature for 4 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (3×30 mL), dried (Na₂SO₄), concentrated and chromatographed over silica gel (50% EtOAc in hexanes) to yield 77.6 mg of pure tosylate 283. Data for 283: MS (ESI) m/z 476.9 (M+H)⁺, 498.9 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.76 (d, J=9 Hz, 2H), 7.46 (ddd, J=2, 5, 11 Hz, 1H), 7.38-7.23 (m, 4H), 6.89-6.83 (m, 1H), 5.73 (s, 1H), 5.04-4.96 (m, 1H), 4.52 (dd, J=4, 12 Hz, 1H), 4.44 (dd, J=5, 11 Hz, 1H), 4.26 (t, J=6 Hz, 2H), 4.16 (t, J=9 Hz, 1H), 3.96 (dd, J=6, 9 Hz, 1H), 3.02 (t, J=6 Hz, 2H), 2.45 (s, 3H).

Synthesis of Isoxazole 214

A suspension of N-desmethylazithromycin 171 (100 mg, 0.136 mmol), tosylate 283 (52 mg, 0.109 mmol), i-Pr₂NEt (3 mL) and NaI (cat.) in THF (4 mL) was heated to reflux for 72 h. The reaction mixture was concentrated and chromatographed over silica gel (methylene chloride:MeOH:NH₄OH=12:1:0.01) to yield 7 mg of 214. Data for 214: MS (ESI) m/z 1039.1 (M+H)⁺, 1061.5 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.46 (ddd, J=2, 5, 11 Hz, 1H), 7.38-7.23 (m, 2H), 6.86 (brt, 1H), 5.72 (s, 1H), 5.08 (d, J=5 Hz, 1H), 5.02-4.96 (m, 1H), 4.68 (d, J=8 Hz, 1H), 4.53 (dd, J=4, 11 Hz, 1H), 4.46 (dd, J=5, 9 Hz, 1H), 0.90 (t, J=6 Hz, 3H).

Example 24 Synthesis of Triazole 215

Scheme 48 exemplifies the synthesis of triazole 215. The cycloaddition of known azide 284 (see U.S. Pat. No. 6,124,334) and alkyne 173 afforded triazole 215.

Synthesis of Triazole 215

A solution of alkyne 173 (0.100 g, 0.13 mmol) and azide 284 (0.046 g, 0.19 mmol) in tetrahydrofuran (1.3 mL) was treated with N,N-diisopropylethylamine (0.670 mL, 3.8 mmol) and copper (I) iodide (36 mg, 0.19 mmol) and the mixture was stirred under argon at 23° C. for 2.5 h. The reaction mixture was diluted with saturated aqueous ammonium hydroxide (10 mL) and extracted with dichloromethane (4×30 mL). The combined organic fractions were dried (Na₂SO₄), evaporated, and the residue purified by flash chromatography (SiO₂, ammonium hydroxide/methanol/dichloromethane 0.05:1:9) to provide 215 (53 mg, 0.048 mmol, 38%) as a white powder. Data for 215: MS (ESI) m/z 545.0 (M+2H)₂ ⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.81 (s, 1H), 7.61-7.54 (m, 1H), 7.39-7.33 (m, 1H), 7.21-7.15 (m, 1H), 6.99 (d, J=2 Hz, 2H), 6.34 (d, J=1 Hz, 2H), 3.29 (s, 3H), 3.26 (s, 3H), 0.89-0.78 (m, 6H).

Example 25 Synthesis of Triazole 216

Scheme 49 depicts the synthesis of triazole 216. The known alcohol 285 (see International Patent Application WO0306440) is converted by standard chemistry to azide 287. This azide is coupled to 4-cyanophenylboronic acid using the Suzuki reaction to afford biaryl azide 288. Cycloaddition of 288 with alkyne 173 afforded triazole 216.

Synthesis of Mesylate 286

A solution of alcohol 285 (2.5 g, 7.4 mmol) in methylene chloride (40 mL) was cooled to 0° C. under argon and treated with Et₃N (1.80 mL, 13.2 mmol) and methanesulfonyl chloride (0.57 mL, 7.4 mmol). The reaction mixture was warmed to 23° C. for 0.5 h then washed with 1 M hydrochloric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL). Drying (Na₂SO₄) and evaporation provided mesylate 286 (2.8 g, 6.7 mmol, 91%) as a white powder Data for 286: ¹HNMR (300 MHz, DMSO-d₆): δ 7.85 (dd, J=9, 8 Hz, 1H), 7.57 (dd, J=11, 2 Hz, 1H), 7.22 (dd, J=9, 2 Hz, 1H), 5.07-5.00 (m, 1H), 4.53-4.48 (m, 2H), 4.22-4.19 (m, 1H), 3.83 (dd, J=9, 6 Hz, 1H), 3.26 (s, 3H).

Synthesis of Azide 287

A solution of mesylate 286 (7.00 g, 16.8 mmol) in dimethylformamide (50 mL) was treated with sodium azide (1.5 g, 23 mmol) and stirred at 50° C. under argon for 18 h. The reaction mixture was cooled to 20° C., poured into H₂O (400 mL) and stirred at 0° C. The resulting precipitate was filtered, washed with H₂O and dried under reduced pressure to provide azide 287 as a white powder (4.0 g, 11 mmol, 66%). Data for 287: ¹HNMR (300 MHz, CDCl₃): δ 7.71 (dd, J=9, 7 Hz, 1H), 7.48 (dd, J=10, 2 Hz, 1H), 7.06 (dd, J=9, 2 Hz, 1H), 4.89-4.77 (m, 1H), 4.09-4.04 (m, 1H), 3.84 (dd, J=9, 6 Hz, 1H), 3.73 (dd, J=13, 5 Hz, 1H), 3.61 (dd, J=13, 5 Hz, 1H).

Synthesis of Azide 288

A solution of azide 287 (0.36 g, 1.0 mmol) in toluene/ethanol/H₂O (3:1:1, 10 mL) was treated with potassium carbonate (0.41 g, 3.0 mmol), 4-cyanophenylboronic acid (0.18 g, 1.2 mmol) and tetrakis(triphenylphosphine)palladium (0.005 g, 0.05 mmol), and the mixture was stirred under argon at 80° C. for 0.5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with H₂O (3×50 mL), dried (Na₂SO₄), and evaporated. Flash chromatography (SiO₂, hexanes/ethyl acetate 1:1) provided azide 288 (0.23 g, 0.67 mmol, 67%) as a white powder. Data for 288: ¹HNMR (300 MHz, CDCl₃): δ 7.72-7.69 (m, 2H), 7.64-7.60 (m, 2H), 7.55 (dd, J=13, 2 Hz), 7.46-7.41 (m, 1H), 7.35 (dd, J=9, 2 Hz), 4.87-4.78 (m, 1H), 4.14-4.08 (m, 1H), 3.89 (dd, J=9, 6 Hz, 1H), 3.73 (dd, J=13, 5 Hz, 1H) 3.61 (dd, J=13, 5 Hz, 1H).

Synthesis of Triazole 216

A solution of alkyne 173 (0.19 g, 0.24 mmol) and azide 288 (0.10 g, 0.30 mmol) in tetrahydrofuran (5.0 mL) was treated with N,N-diisopropylethylamine (0.042 mL, 0.24 mmol) and copper (I) iodide (19 mg, 0.10 mmol) and the mixture was stirred under argon at 23° C. for 0.5 h. The reaction mixture was diluted with saturated aqueous ammonium hydroxide (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic fractions were dried (Na₂SO₄) and evaporated, and the residue purified by flash chromatography (SiO₂, ammonium hydroxide/methanol/dichloromethane (0.05:1:9) to provide 216 (110 mg, 0.098 mmol, 41%) as a white powder. Data for 216: MS (ESI) m/z 1125 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.72-7.69 (m, 2H), 7.62 (s, 1H), 7.60 (m, 2H), 7.49-7.44 (m, 1H), 7.42-7.37 (m, 1H), 7.22-7.19 (m, 1H), 3.31 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 0.88-0.86 (m, 6H).

Example 26 Synthesis of Triazoles 217 and 218

Scheme 50 details the synthesis of triazoles 217 and 218. The known carbamate 289 (see J. Med. Chem. 2000, 43, 953) was deprotected to afford aniline 290. Diazotization of 290 afforded azide 291, which was subsequently converted by cycloaddition chemistry with available alkynes to triazoles 292 and 295. Manipulation of these intermediates to azides 294 and 297 was followed by cycloaddition with alkyne 173 to afford triazoles 217 and 218 respectively.

Synthesis of Aniline 290

A solution of carbamate 289 (3.6 g, 7.9 mmol) in methanol (120 mL) was treated with acetic acid (30 mL) and 10% PdC (1.0 g) and the mixture was stirred under a balloon of hydrogen for 12 h at 23° C. The reaction mixture was filtered through a plug of SiO₂ and evaporated under reduced pressure, providing 290 (1.5 g, 6.6 mmol, 84%) as a pink-white solid. Data for 290: ¹HNMR (300 MHz, DMSO-d₆): δ 7.32 (dd, J=14, 3, Hz, 1H), 6.99-6.95 (m, 1H), 6.75 (dd, J=10, 9 Hz, 1H), 4.99 (s, 2H), 4.66-4.58 (m, 1H), 4.01-3.94 (m, 1H), 3.72 (dd, J=9, 6 Hz, 1H), 3.63 (dd, J=12, 4 Hz, 1H), 3.50 (dd, J=12, 4 Hz, 1H).

Synthesis of Azide 291

A suspension of aniline 290 (0.56 g, 2.5 mmol) in H₂O (10 mL) was cooled to 0° C. and treated with concentrated hydrochloric acid (1.0 mL, 12.4 mmol) and sodium nitrite (0.19 g, 2.8 mmol). A solution of sodium azide (0.24 g, 3.8 mmol) in H₂O (1.0 mL) was added after 1 h, and stirring at 0° C. was continued for an additional 1 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (100 mL). The organic fraction was washed with H₂O (100 mL) dried (Na₂SO₄) and evaporated to an orange film. Data for 291: ¹HNMR (300 MHz, CD₃OD): δ 7.51 (dd, J=14, 3 Hz, 1H), 7.19 (m, 1H), 7.03 (m, 1H), 4.70-4.61 (m, 1H), 4.02-3.96 (m, 1H), 3.79 (m, 1H), 3.74 (m, 1H).

Synthesis of Triazole 292

A solution of azide 291 (0.14 g, 0.56 mmol) and trimethylsilylacetylene (0.47 mL, 3.3 mmol) in dimethylformamide (4 mL) was stirred at 60° C. for 16 h. The reaction mixture was cooled to 23° C., concentrated under reduced pressure to a volume of 2.0 mL, and treated with tetrabutylammonium fluoride (1.5 mL of a 1.0 M solution in tetrahydrofuran) and acetic acid (0.1 mL) and the mixture was stirred for 12 h. Ethyl acetate (100 mL) was added and the solution was washed with H₂O (3×75 mL), dried (Na₂SO₄) and evaporated to provide 292 (87 mg, 0.31 mmol, 56%) as a brown foam that was used directly in the next step.

Synthesis of Azide 294

A solution of alcohol 292 (94 mg, 0.34 mmol) in dichloromethane (3.5 mL) was cooled to 0° C. and treated with triethylamine (0.095 mL, 0.68 mmol) and methanesulfonyl chloride (0.029 mL, 0.37 mmol). The reaction mixture was stirred at 23° C. for 1 h, then diluted with ethyl acetate (150 mL) and washed with 1 M hydrochloric acid (2×75 mL), 10% aqueous sodium carbonate (75 mL), dried (Na₂SO₄), and evaporated. Flash chromatography (SiO₂, 50-100% ethyl acetate/hexanes) provided mesylate 293 (50 mg, 0.14 mmol, 41%) as a yellow film. Data for 293: MS (ESI) m/z 357 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 8.11-8.09 (m, 1H), 8.04-7.98 (m, 1H), 7.88 (m, 1H), 7.85 (dd, J=13, 2 Hz, 1H), 7.32-7.27 (m, 1H), 5.04-4.96 (m, 1H), 4.54 (dd, J=12, 4 Hz, 1H), 4.47 (dd, J=12, 4 Hz, 1H), 4.26-4.20 (m, 1H), 4.03 (dd, J=9, 6 Hz, 1H), 3.12 (s, 3H), 2.36 (s, 6H).

A solution of mesylate 293 (0.050 g, 0.15 mmol) in dimethylformamide (1.5 mL) was treated with sodium azide (0.018 g, 0.28 mmol) and stirred at 60° C. under argon for 12 h. The reaction mixture was cooled to 20° C., diluted with ethyl acetate (75 mL), washed with H₂O (3×50 mL), dried (Na₂SO₄), and evaporated under reduced pressure providing azide 294 as a yellow film (41 mg).

Synthesis of Triazole 217

A solution of crude azide 294 obtained above (0.038 g, 0.13 mmol) and alkyne 173 (0.079 g, 0.10 mmol) in tetrahydrofuran (5.0 mL) was treated with diisopropylethylamine (0.050 mL, 0.29 mmol) and copper (I) iodide (18 mg, 0.094 mmol) and stirred under argon at 23° C. for 1 h. The reaction mixture was diluted with saturated aqueous ammonium hydroxide (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic fractions were dried (Na₂SO₄), evaporated, and the residue purified by flash chromatography (SiO₂, ammonium hydroxide/methanol/dichloromethane (0.05:1:9) to provide triazole 217 (32 mg, 0.029 mmol, 29%) as a yellow foam. Data for 217: MS (ESI) m/z 546 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.01 (d, J=1 Hz, 1H), 7.88-7.83 (m, 1H), 7.79 (d, J=1 Hz, 1H), 7.68 (s, 1H), 7.60 (m, 1H), 7.20 (m, 1H), 3.26 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 0.88-0.84 (m, 6H).

Synthesis of Triazole 295

A solution of azide 291 (0.14 g, 0.56 mmol) and N,N-dimethylpropargylamine (0.30 mL, 2.6 mmol) in dimethylformamide (4 mL) was treated with copper (I) iodide (0.030 g, 0.16 mmol) and stirred at 20° C. for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 10% ammonium hydroxide (2×100 mL) and saturated aqueous sodium chloride (100 mL), dried (Na₂SO₄) and evaporated. Flash chromatography of the crude material (SiO₂, ammonium hydroxide/methanol/dichloromethane (0.05:1:9) provided triazole 295 (18 mg, 0.054 mmol, 9.6%) as a yellow film. Data for 295: ¹HNMR (300 MHz, CDCl₃): δ 8.02-8.01 (m, 1H), 7.86-7.81 (m, 1H), 7.71 (dd, J=14, 2 Hz, 1H), 7.33-7.27 (m, 1H), 4.83-4.76 (m, 1H), 4.15-4.04 (m, 2H), 4.02 (dd, J=9, 4 Hz, 1H), 3.78 (dd, J=13, 3 Hz, 1H), 3.73-3.71 (m, 2H), 2.36 (s, 6H).

Synthesis of Azide 297

A solution of alcohol 295 (17 mg, 0.050 mmol) in dichloromethane (0.5 mL) was cooled to 0° C. and treated with triethylamine (0.014 mL, 0.10 mmol) and methanesulfonyl chloride (0.0043 mL, 0.056 mmol). The reaction mixture was stirred at 23° C. for 1 h, then diluted with ethyl acetate (100 mL) and washed with 10% aqueous sodium carbonate (2×100 mL), dried (Na₂SO₄) and evaporated. Flash chromatography (SiO₂, ammonium hydroxide/methanol/dichlromethane (0.05:1:9) provided mesylate 296 (17 mg, 0.041 mmol, 82%) as a yellow film. Data for 296: MS (ESI) m/z 414 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 8.02-8.01 (m, 1H), 8.05-7.95 (m, 1H), 7.83 (dd, J=13, 2 Hz, 1H), 7.31-7.27 (m, 1H), 5.04-4.97 (m, 1H), 4.54 (dd, J=12, 4 Hz, 1H), 4.47 (dd, J=12, 4 Hz, 1H), 4.03 (dd, J=9, 6 Hz, 1H), 3.70 (s, 2H), 3.12 (s, 3H), 2.36 (s, 6H).

A solution of the above mesylate 296 (0.017 g, 0.042 mmol) in dimethylformamide (0.40 mL) was treated with sodium azide (0.006 g, 0.848 mmol) and stirred at 60° C. under argon for 12 h. The reaction mixture was cooled to 20° C., diluted with ethyl acetate (75 mL), washed with H₂O (3×50 mL), dried (Na₂SO₄), and evaporated under reduced pressure providing azide 297 as a white foam (15 mg).

Synthesis of Triazole 218

A solution of crude azide 297 (0.012 g, 0.033 mmol) and alkyne 173 (0.021 g, 0.027 mmol) in tetrahydrofuran (1.4 mL) was treated with diisopropylethylamine (0.014 mL, 0.13 mmol) and copper (I) iodide (4.7 mg, 0.025 mmol) and stirred under argon at 23° C. for 1 h. The reaction mixture was diluted with saturated aqueous ammonium hydroxide (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic fractions were dried (Na₂SO₄), evaporated, and the residue purified by flash chromatography (SiO₂, ammonium hydroxide/methanol/dichloromethane (0.05:1:9) to provide triazole 218 (12 mg, 0.010 mmol, 39%) as a yellow foam. Data for 218: MS (ESI) m/z 574 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.11 (m, 1H), 7.89-7.84 (m, 1H), 7.67 (s, 1H), 7.58 (m, 1H), 7.20 (m, 1H), 3.22 (s, 3H), 2.38 (s, 6H), 2.31 (s, 3H), 2.23 (s, 3H), 0.88-0.84 (m, 6H).

Example 27 Synthesis of Triazoles 219 and 220

Scheme 51 details the synthesis of triazoles 219 and 220. Iodoaryl alcohol 285 is converted to nitrile 298 which is then transformed to azide 300 via mesylate 299. Cycloaddition of azide 300 and alkyne 173 yielded triazole 219. Nitrile 298 was manipulated to oxadiazole 301, which served as the precursor to azide 302. Cycloaddition of 302 with 173 afforded triazole 220.

Synthesis of Nitrile 298

A solution of alcohol 285 (5.4 g, 16.1 mmol) in dimethylformamide (116 mL) was treated with copper (1) cyanide (1.60 g, 17.7 mmol) and stirred at 145° C. under argon for 18 h. The reaction mixture was cooled to 23° C. and diluted with methylene chloride (1100 mL), and washed with saturated aqueous ammonium chloride (100 mL) and saturated aqueous sodium chloride (1100 mL). Drying (Na₂SO₄) and evaporation provided 298 (2.9 g, 12.3 mmol, 76%) as a white powder, Data for 298: ¹HNMR (300 MHz, CD₃OD): δ 7.68 (dd, J=12, 2 Hz, 1H), 7.62 (dd, J=9, 8 Hz, 1H), 7.39 (dd, J=9, 2 Hz, 1H), 4.71-4.65 (m, 1H), 4.08-4.02 (m, 1H), 3.86 (dd, J=9, 6 Hz, 1H), 3.77 (dd, J=13, 3 Hz, 1H), 3.60 (dd, J=13, 4 Hz, 1H).

Synthesis of Azide 300

A solution of nitrile alcohol 298 (600 mg, 2.50 mmol) in methylene chloride (14 mL) was cooled to 0° C. under argon and treated with triethylamine (0.70 mL, 5.0 mmol) and methanesulfonyl chloride (0.22 mL, 2.8 mmol). The reaction mixture was warmed to 23° C. for 0.5 h and subsequently diluted with methylene chloride (50 mL), washed with 1 M hydrochloric acid (15 mL), saturated aqueous sodium bicarbonate (15 mL), and saturated aqueous sodium chloride (15 mL). Drying (Na₂SO₄) and evaporation provided mesylate 299 (0.62 g, 2.0 mmol, 80%) as a white powder. Data for 299: ¹HNMR (300 MHz, CDCl₃): δ 7.63 (dd, J=12, 2 Hz, 1H), 7.56 (dd, J=9, 7 Hz, 1H), 7.31 (dd, J=9, 2 Hz, 1H), 5.01-4.94 (m, 1H), 4.51 (dd, J=12, 3 Hz, 1H), 4.43 (dd, J=12, 4 Hz, 1H), 4.22-4.15 (m, 1H), 3.96 (dd, J=9, 6 Hz, 1H), 3.45 (dd, J=15, 7 Hz, 1H), 3.06 (s, 3H).

A solution of mesylate 299 (0.61 g, 1.9 mmol) in dimethylformamide (15 mL) was treated with sodium azide (0.26 g, 4.0 mmol) and stirred at 75° C. under argon for 1 h. The reaction mixture was cooled to 23° C., diluted with water (100 mL) and extracted with methylene chloride (3×50 mL). The combined organic layer was washed with water (100 mL). The solvent was evaporated and the residue redissolved in ethyl acetate (50 mL) and washed with water (100 mL). Drying (Na₂SO₄) and evaporation provided azide 300 (0.38 g, 1.5 mmol, 79%) as a brown oil. Data for 300: ¹HNMR (300 MHz, CDCl₃): δ 7.61-7.52 (m, 2H), 7.28 (dd, J=9, 2 Hz, 1H), 4.84-4.76 (m, 1H), 4.08-4.02 (m, 1H), 3.83 (dd, J=9, 6 Hz, 1H), 3.72 (dd, J=13, 4 Hz, 1H), 3.55 (dd, J=13, 4 Hz, 1H).

Synthesis of Triazole 219

A solution of alkyne 173 (0.15 g, 0.19 mmol) and azide 300 (0.060 g, 0.21 mmol) in tetrahydrofuran (1.5 mL) was treated with N,N-diisopropylethylamine (0.066 mL, 0.38 mmol) and copper (I) iodide (19 mg, 0.10 mmol) and stirred under argon at 23° C. for 1 h. The reaction mixture was diluted with saturated aqueous ammonium hydroxide (10 mL) and extracted with dichloromethane (4×30 mL). The combined organic fractions were dried (Na₂SO₄), evaporated, and the residue purified by flash chromatography (SiO₂, ammonium hydroxide/methanol/dichloromethane (0.05:1:9) to provide 219 (100 mg, 0.095 mmol, 50%) as a white powder. Data for 219: ¹HNMR (300 MHz, CDCl₃, partial): δ 7.62-7.55 (m, 3H), 7.24 (dd, J=9, 2 Hz, 1H), 3.34 (s, 3H), 2.32 (s, 3H), 2.24 (s, 3H), 1.02 (d, J=7 Hz, 3H), 0.92-0.80 (m, 6H).

Synthesis of oxadiazole 301

A solution of nitrile 298 (2.00 g, 8.50 mmol) in methanol (42.5 mL) was treated with potassium carbonate (1.18 g, 8.50 mmol) and hydroxylamine hydrochloride (1.18 g, 17.0 mmol) and heated to reflux for 18 h. The reaction mixture was cooled to 23° C., diluted with ethyl acetate (100 mL) and washed with water (4×100 mL). Drying (Na₂SO₄) and evaporation afforded a brown powder. A solution of crude this hydroxyamidine (1.00 g, 3.7 mmol) in pyridine (17.5 mL) under argon was cooled to 0° C. and treated dropwise with a solution of acetic anhydride (0.70 mL, 7.4 mmol) in pyridine (17.5 mL). The reaction mixture was heated to 120° C. for 1 h and then cooled to 23° C. The reaction mixture was then diluted with ethyl acetate (50 mL) and washed with 1 M hydrochloric acid (30 mL), saturated aqueous sodium bicarbonate (30 mL), and saturated aqueous sodium chloride (30 mL) and dried (Na₂SO₄). Flash chromatography (SiO₂, 50-75% ethyl acetate/hexanes) afforded the intermediate acetate-protected oxadiazole (0.28 g, 0.84 mmol, 22%) as a white powder. Data for intermediate oxadiazole: MS (ESI) m/z 335.9 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃: δ 8.07-8.02 (m, 1H), 7.62 (dd, J=13, 2 Hz, 1H), 7.39 (dd, J=9, 2 Hz, 1H), 4.97-4.89 (m, 1H), 4.41 (dd, J=12, 4 Hz, 1H), 4.33 (dd, J=12, 5 Hz, 1H), 4.21-4.15 (m, 1H), 3.88 (dd, J=9, 6 Hz, 1H), 2.68 (s, 3H), 2.11 (s, 3H).

A solution of the oxadiazole acetate obtained above (0.25 g, 0.75 mmol) in methanol (0.75 mL) was treated with sodium methoxide (0.005 mg, 0.08 mmol) and stirred at 23° C. for 1 h. The reaction mixture was quenched with 1 M hydrochloric acid (0.15 mL) and the solvent was evaporated in vacuo to provide oxadiazole 301 (0.21 g, 0.72 mmol, 95%) as a white powder. Data for 301: ¹HNMR (300 MHz, CDCl₃): δ 8.06-8.00 (m, 1H), 7.63 (dd, J=13, 2 Hz, 1H), 7.39 (dd, J=9, 2 Hz, 1H), 4.81 (m, 1H), 4.07 (m, 3H), 3.78 (dd, J=13, 4 Hz, 1H), 2.68 (s, 1H).

Synthesis of Azide 302

A solution of alcohol 301 (0.18 g, 0.61 mmol) in methylene chloride (3.5 mL) was cooled to 0° C. under argon and treated with triethylamine (0.18 mL, 1.2 mmol) and methanesulfonyl chloride (0.050 mL, 0.68 mmol). The reaction mixture was warmed to 23° C. for 0.5 h and diluted with methylene chloride (20 mL), washed with 1 M hydrochloric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and saturated aqueous sodium chloride (10 mL). Drying (Na₂SO₄) and evaporation provided the intermediate mesylate (0.19 g, 0.51 mmol, 84%) as a white powder: ¹HNMR (300 MHz, CDCl₃, partial): δ 8.02-7.96 (m, 1H), 7.62-7.45 (m, 1H), 4.94-4.87 (m, 1H), 4.46 (dd, J=12, 4 Hz, 1H), 4.39 (dd, J=12, 4 Hz, 1H), 4.17-4.11 (m, 1H), 3.95 (dd, J=9, 6 Hz, 1H), 3.05 (s, 3H), 2.61 (s, 3H).

A solution of the above mesylate (0.18 g, 0.49 mmol) in dimethylformamide (3.7 mL) was treated with sodium azide (64 mg, 0.98 mmol) and stirred at 75° C. under argon for 2 h. The reaction mixture was cooled to 23° C., poured into H₂O (50 mL), and stirred at 0° C. The resulting precipitate was filtered, washed with H₂O, and dried under reduced pressure to provide azide 302 (80 mg, 0.25 mmol, 51%) as a white powder. Data for 302: ¹HNMR (300 MHz, CDCl₃): δ 8.05 (m, 1H), 7.62 (dd, J=13, 2 Hz, 1H), 7.41-7.39 (m, 1H), 4.88-4.81 (m, 1H), 4.16-4.10 (m, 1H), 3.92 (dd, J=9, 6 Hz, 1H), 3.76 (dd, J=13, 5 Hz, 1H), 3.63 (dd, J=13, 4 Hz, 1H), 2.68 (s, 3H).

Synthesis of Triazole 220

A solution of alkyne 173 (0.13 g, 0.16 mmol) and azide 302 (0.060 g, 0.19 mmol) in tetrahydrofuran (1.2 mL) was treated with N,N-diisopropylethylamine (0.044 mL, 0.32 mmol) and copper (I) iodide (15 mg, 0.080 mmol) and stirred under argon at 23° C. for 0.5 h. The reaction mixture was diluted with saturated aqueous ammonium hydroxide (10 mL) and extracted with dichloromethane (4×30 mL). The combined organic fractions were dried (Na₂SO₄), evaporated, and the residue purified by flash chromatography (SiO₂, ammonium hydroxide/methanol/dichloromethane (0.05:1:9)) to provide 220 (70 mg, 0.063 mmol, 40%) as a white powder. Data for 220: MS (ESI) m/z 1105.5 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.04-7.98 (m, 1H), 7.65 (s, 1H), 7.57-7.53 (m, 1H), 7.27-7.24 (m, 1H), 4.81-4.68 (m, 1H), 4.76-4.73 (m, 1H), 4.43 (d, J=7 Hz, 1H), 3.35 (s, 3H), 0.99-0.81 (m, 6H).

Example 28 Synthesis of Triazole 221

Scheme 52 details the synthesis of triazole 221. p-Nitrobenzenesulfonyl chloride was treated with ammonia to provide sulfonamide 303. The nitro group was reduced to provide aniline 304 which was converted to carbamate 305. Oxazolidinone formation to yield alcohol 306 was followed by standard manipulations to afford azide 308. Cycloaddition of 308 with alkyne 173 yielded triazole 221.

Synthesis of Sulfonamide 303

4-Nitrobenzenesulfonyl chloride (2.22 g, 10 mmol) was added to a solution of concentrated ammonium hydroxide (3 mL) in THF (5 mL) at 0° C. The reaction was stirred at 0° C. for 1 h and then at room temperature for additional 1 h. The THF was removed under vacuum, more water was added, and the precipitate was collected by filtration and dried to afford 303 (1.90 g, 94% yield).

Synthesis of Aniline 304

To a solution of 4-nitrobenzenesulfonamide 303 (1.9 g, 9.4 mmol) in methanol (20 mL) was added 10% Pd—C (0.19 g) and the resulted mixture was stirred at room temperature for 12 h under 1 atm hydrogen atmosphere. The Pd—C was removed by filtration on celite. The filtered solution was evaporated to provide 304 (1.4 g, 87% yield) as a white solid. Data for 304: ¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 7.63 (d, J=9 Hz, 2H), 6.70 (d, J=9 Hz, 2H).

Synthesis of Carbamate 305

Benzyl chloroformate (1.4 mL, 9.6 mmol) was added dropwise to a solution of aniline 304 (1.38 g, 8.0 mmol), and NaHCO₃ (2.69 g, 21 mmol) in a mixture of THF (5 mL) and water (3 mL) at 0° C. After stirring at same temperature 2 h, the reaction mixture was diluted with ethyl acetate (30 mL). The organic layer was washed with brine (3×50 mL), dried (MgSO₄) and concentrated to provide 2.35 g of white solid 305 in a yield of 96%. Data for 305: ¹HNMR (300 MHz, CD₃OD): δ 7.80 (d, J=9 Hz, 2H), 7.61 (d, J=9 Hz, 2H), 7.43-7.33 (m, 5H), 5.20 (s, 2H).

Synthesis of Alcohol 306

To a solution of carbamate 305 (440 mg, 1.44 mmol) in THF (10 mL) was added n-BuLi (2.0 mL, 2.5 M in hexane, 5.03 mmol) at −78° C. and the mixture was stirred for 30 min. (R)-(−)-Glycidyl butyrate (0.25 mL, 1.73 mmol) was added, the reaction was stirred at −78° C. for 3 h, and then warmed to room temperature and stirred overnight. The reaction was carefully quenched with saturated NH₄Cl and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO₄) and concentrated. The residue was dissolved in 10 mL of methanol and sodium methoxide (0.2 mL, 30% wt/wt in methanol) was added. After stirring at room temperature for 2 h, the mixture was concentrated and purified by chromatography (25:1:0.05/CH₂Cl₂:MeOH: NH₃.H₂O) to afford 100 mg of desired oxazolidinone 306 in a yield of 26%. Data for 306: ¹HNMR (300 MHz, CD₃OD): δ 7.90 (d, J=9 Hz, 2H), 7.78 (d, J=9 Hz, 2H), 4.77 (m, 1H), 4.18 (t, J=9 Hz, 1H), 3.99 (dd, J=6, 9 Hz, 1H), 3.87 (dd, J=3, 12 Hz, 1H), 3.71 (dd, J=3, 12 Hz, 1H).

Synthesis of Azide 308

To a solution of alcohol 306 (106 mg, 0.39 mmol), Et₃N (129 mg, 1.28 mmol) and 4-dimethylaminopyridine (1 mg) in CH₂Cl₂ (10 mL) and DMF (2 mL) was added methanesulfonyl chloride (150 mg, 1.31 mmol) at 0° C., and the mixture was stirred for 2 h. The reaction mixture was concentrated and purified by chromatography on silica gel (10:1:0.05/CH₂Cl₂:MeOH:NH₃.H₂O) to afford mesylate 307 (135 mg, 81% yield). Data for 307: ¹HNMR (300 MHz, CDCl₃): δ 7.85 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 4.96 (m, 1H), 4.50 (dd, J=3, 12 Hz, 1H), 4.42 (dd, J=3, 12 Hz, 1H), 4.16 (t, J=9 Hz, 1H), 3.89 (dd, J=6, 9 Hz, 1H), 2.90 (s, 3H), 2.80 (s, 3H).

A mixture of 307 (135 mg, 0.30 mmol) and sodium azide (101 mg, 1.56 mmol) in DMF (1 mL) was heated at 80° C. for 2 h. The reaction mixture was diluted with CH₂Cl₂ (10 mL), filtered, concentrated and purified by flash chromatography to afford crude azide 308 (118 mg), which was of sufficient purity to be used in subsequent reactions. Data for 308: ¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 7.73 (d, J=8 Hz, 2H), 7.43 (d, J=8 Hz, 2H), 4.67 (m, 1H), 3.97 (t, J=9 Hz, 1H), 3.71 (dd, J=7, 8 Hz, 1H), 3.57 (dd, J=3, 13 Hz, 1H), 3.41 (dd, J=4, 13 Hz, 1H), 2.76 (s, 3H).

Synthesis of Triazole 221

A mixture of alkyne 173 (118 mg, 0.15 mmol), azide 308 (118 mg, prepared as above) and copper (I) iodide (28.5 mg, 0.15 mmol) in THF (5 mL) was repeatedly degassed and flushed with argon. i-Pr₂NEt (0.26 mL) was introduced and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into saturated NH₄Cl (30 mL) and stirred for 15 minutes. The mixture was extracted with CH₂Cl₂, washed with brine, dried over MgSO₄ and concentrated. The crude material was chromatographed on silica gel (10:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) to provide triazole 221 (108 mg, 62% yield) as a white foam. Data for 221: MS (ESI) m/z 1162.3 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃-DMSO, partial): δ 7.91 (d, J=9 Hz, 2H), 7.85 (s, 1H), 7.51 (d, J=9 Hz, 2H), 3.35 (s, 3H), 3.33 (s, 3H), 3.32 (s, 3H), 0.89 (t, J=8 Hz, 3H).

Example 29 Synthesis of Triazole 222

Scheme 53 details the synthesis of triazole 222. Sulfonamide 309 was protected as the sulfonamidine 310 prior to conversion to oxazolidinone alcohol 311. Alcohol 311 was transformed to azide 314 via functional group interconversion followed by hydrolysis of the amidine protecting group. Cycloaddition of 314 with alkyne 173 provided triazole 222.

Synthesis of Sulfonamidine 310

A solution of sulfonamide 309 (1.10 g, 3.59 mmol, prepared from 3-nitrobenzenesulfonyl chloride by using similar procedures described for the preparation of 305), thionyl chloride (1.30 mL, 17.97 mmol) and DMF (5 mL) in CH₂Cl₂ (20 mL) was refluxed for 0.5 h. The reaction was cooled with an ice-bath and neutralized with saturated NaHCO₃. The organic phase was separated, washed with brine, dried over MgSO₄ and evaporated to provide 310 as a white solid (1.25 g, 96% yield). Data for 310: ¹HNMR (300 MHz, CDCl₃): δ 8.12 (s, 1H), 7.81 (t, J=4 Hz, 1H), 7.74 (m, 1H), 7.59 (m, 1H), 7.44-7.35 (m, 6H), 6.98 (br s, 1H), 5.22 (s, 2H), 3.12 (s, 3H), 3.02 (s, 3H).

Synthesis of Alcohol 311

To a solution of 310 (724 mg, 2.0 mmol) in THF (16 mL) was added n-BuLi (1.5 mL, 2.5 M in hexane, 3.5 mmol) at −78° C. and the mixture was stirred for 30 min. (R)-(−)-Glycidyl butyrate (0.35 mL, 2.5 mmol) was added, the reaction was stirred at −78° C. for 3 h, and then warmed to room temperature and stirred overnight. The reaction was carefully quenched with saturated NH₄Cl and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO₄) and concentrated. The residue was dissolved in 10 mL of methanol and sodium methoxide (0.2 mL, 30% wt/wt in methanol) was added. After stirring at room temperature for 2 h, the mixture was concentrated and purified by chromatography on silica gel (25:1:0.05/CH₂Cl₂:MeOH:NH₃.H₂O) to afford 311 as a white solid (350 mg, 53% yield). Data for 311: ¹HNMR (300 MHz, CDCl₃): δ 8.06 (s, 1H), 7.87 (dd, J=2, 8 Hz, 1H), 7.79 (t, J=2 Hz, 1H), 7.57 (m, 1H), 7.39 (t, J=8 Hz, 1H), 4.70 (m, 1H), 3.99 (m, 2H), 3.92 (dd, J=3, 12 Hz, 1H), 3.70 (dd, J=4, 12 Hz, 1H), 3.08 (s, 3H), 2.96 (s, 3H).

Synthesis of Azide 314

To a solution of alcohol 311 (170 mg, 0.52 mmol) and Et₃N (58 mg, 0.57 mmol) in CH₂Cl₂ (10 mL) was added methanesulfonyl chloride (72 mg, 0.62 mmol) at 0° C. and the mixture was stirred for 30 min. The CH₂Cl₂ solution was washed with brine, dried (MgSO₄) and concentrated to afford mesylate 312 (200 mg, 95% yield). Data for 312: ¹HNMR (300 MHz, CDCl₃): δ 8.05 (s, 1H), 7.79 (m, 2H), 7.56 (d, J=8 Hz, 1H), 7.39 (t, J=8 Hz, 1H), 4.90 (m, 1H), 4.45 (dd, J=4, 12 Hz, 1H), 4.37 (dd, J=4, 12 Hz, 1H), 4.14 (t, J=9 Hz, 1H), 3.91 (dd, J=6, 9 Hz, 1H), 3.08 (s, 3H), 3.03 (s, 3H), 2.95 (s, 3H).

A mixture of mesylate 312 (105 mg, 0.26 mmol) and sodium azide (67 mg, 1.04 mmol) in DMF (2 mL) was heated at 80° C. for 2 h. The reaction was then diluted with ethyl acetate, washed with brine, dried (MgSO₄) and evaporated to provide azide 313 as a white solid (80 mg, 87% yield). Data for 313: ¹HNMR (300 MHz, CDCl₃): δ 8.06 (s, 1H), 7.84 (m, 1H), 7.78 (t, J=2 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 4.77 (m, 1H), 4.07 (t, J=9 Hz, 1H), 3.84 (dd, J=6, 9 Hz, 1H), 3.67 (dd, J=4, 13 Hz, 1H), 3.53 (dd, J=4, 13 Hz, 1H), 3.08 (s, 3H), 2.95 (s, 3H).

To a solution of azide 313 (80 mg, 0.23 mmol) in methanol (5 mL) was added concentrated HCl (0.5 mL). After refluxing for 4 h, the reaction was cooled with an ice-bath and neutralized with saturated NaHCO₃. The resulting mixture was extracted with CH₂Cl₂, washed with brine, dried over MgSO₄ and evaporated to provide 314 (58 mg, 86% yield). Data for 314: ¹HNMR (300 MHz, CDCl₃—CD₃OD): δ 7.86 (m, 1H), 7.68 (d, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.39 (t, J=8 Hz, 1H), 4.75 (m, 1H), 4.04 (t, J=9 Hz, 1H), 3.80 (dd, J=6, 9 Hz, 1H), 3.64 (dd, J=4, 13 Hz, 1H), 3.47 (dd, J=4, 13 Hz, 1H).

Synthesis of Triazole 222

To a solution of alkyne 173 (79 mg mg, 0.10 mmol), azide 314 (36 mg, 0.12 mmol) and copper (I) iodide (38 mg, 0.2 mmol) in THF (5 mL) under argon was added i-Pr₂NEt (0.18 mL). After stirring at room temperature for 2 h, the reaction mixture was poured into saturated NH₄Cl (30 mL) and stirred for 15 minutes. The mixture was extracted with CH₂Cl₂, washed with brine, dried over MgSO₄ and concentrated. The crude material was chromatographed on silica (10:1 CH₂Cl₂/MeOH) to provide triazole 222 (65 mg, 60% yield) as a white foam. Data for 222: MS (ESI) m/z 1084.4 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃-DMSO, partial): δ 7.76 (s, 1H), 7.71 (d, J=8 Hz, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.36 (t, J=8 Hz, H), 0.81 (t, J=7 Hz, 3H).

Example 30 Synthesis of Triazoles 223 and 224

Scheme 54 details the synthesis of triazoles 223 and 224. Sulfonamide 305 was protected as sulfonamidine 315 prior to conversion to oxazolidinone alcohol 316. Transformation of 316 to azide 319 as described previously was followed by cycloaddition of 319 with alkyne 173 to produce triazole 223. The cycloaddition of intermediate azide 318 with alkyne 173 afforded triazole 224.

Synthesis of Sulfonamidine 315

Sulfonamidine 315 was synthesized using the same procedure described for the preparation of 310; 0.92 g of 305 afforded 1.02 g of 315 (94% yield). Data for 315: ¹HNMR (300 MHz, CDCl₃): δ 8.10 (s, 1H), 7.81 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.41-7.34 (m, 5H), 6.89 (br s, 1H), 5.20 (s, 2H), 3.11 (s, 3H), 3.00 (s, 3H).

Synthesis of Alcohol 316

Alcohol 316 was synthesized using the same procedure described for the preparation of 311; 0.97 g of 315 afforded 0.60 g of 316 (69% yield). Data for 316: ¹HNMR (300 MHz, CDCl₃—CD₃OD): δ 8.03 (s, 1H), 7.79 (d, J=9 Hz, 2H), 7.59 (d, J=9 Hz, 2H), 4.68 (m, 1H), 3.98 (m, 2H), 3.84 (dd, J=4, 13 Hz, 1H), 3.64 (dd, J=4, 13 Hz, 1H), 3.08 (s, 3H), 2.95 (s, 3H).

Synthesis of Azide 318

Mesylate 317 was synthesized using the same procedure described for the preparation of 312; 176 mg of 316 afforded 210 mg of 317 (96% yield). Data for 317: ¹HNMR (300 MHz, CDCl₃): δ 8.06 (s, 1H), 7.83 (d, J=9 Hz, 2H), 7.57 (d, J=9 Hz, 2H), 4.90 (m, 1H), 4.41 (m, 2H), 4.13 (t, J=9 Hz, 1H), 3.94 (dd, J=6, 9 Hz, 1H), 3.10 (s, 3H), 3.06 (s, 3H), 2.95 (s, 3H).

Azide 318 was synthesized using the same procedure described for the preparation of 313; 210 mg of 317 afforded 180 mg of 318 (98% yield). Data for 318: ¹HNMR (300 MHz, CDCl₃): δ 8.04 (s, 1H), 7.82 (d, J=9 Hz, 2H), 7.60 (d, J=9 Hz, 2H), 4.90 (m, 1H), 4.08 (t, J=9 Hz, 1H), 3.85 (dd, J=6, 9 Hz, 1H), 3.70 (dd, J=4, 13 Hz, 1H), 3.55 (dd, J=4, 13 Hz, 1H), 3.09 (s, 3H), 2.96 (s, 3H).

Synthesis of Azide 319

Azide 319 was synthesized using the same procedure described for the preparation of 314; 150 mg of 318 afforded 118 mg of 319 (93% yield). Data for 319: ¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 7.78 (d, J=9 Hz, 2H), 7.56 (d, J=9 Hz, 2H), 4.74 (m, 1H), 4.04 (t, J=9 Hz, 1H), 3.80 (dd, J=6, 9 Hz, 1H), 3.64 (dd, J=4, 13 Hz, 1H), 3.48 (dd, J=4, 13 Hz, 1H).

Synthesis of Triazole 223

Triazole 223 was synthesized using the same procedure described for the preparation of 222; the reaction of alkyne 173 (118 mg, 0.15 mmol) and azide 319 (54 mg, 0.18 mmol) afforded 150 mg of 223 (92% yield). Data for 223: MS (ESI) m/z 1084.4 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.77 (d, J=9 Hz, 2H), 7.55 (s, 1H), 7.45 (d, J=9 Hz, 2H), 3.26 (s, 3H), 0.82 (t, J=8 Hz, 3H).

Synthesis of Triazole 224

Triazole 224 was synthesized using the same procedure described for the preparation of 222; the reaction of alkyne 173 (79 mg, 0.10 mmol) and azide 318 (43 mg, 0.12 mmol) afforded 93 mg of 224 (82% yield). Data for 224: MS (ESI) m/z 1139.7 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.04 (s, 1H), 7.78 (d, J=9 Hz, 2H), 7.54 (s, 1H), 7.45 (d, J=9 Hz, 2H), 3.27 (s, 3H), 3.07 (s, 3H), 2.94 (s, 3H), 0.82 (t, J=8 Hz, 3H).

Example 31 Synthesis of Triazoles 225-227

Scheme 55 details the synthesis of triazole 225. 3,4-Dichloroaniline was converted to carbamate 320 before being carried further through alcohol 321 to azide 323. The cycloaddition of 323 with alkyne 173 gave triazole 225. Triazoles 226 and 227 were synthesized from the requisite anilines using the same sequence as described in Scheme 55.

Synthesis of Carbamate 320

Sodium bicarbonate (2.60 g, 24.7 mmol) was dissolved in water (22 mL) and 3,4-dichloroaniline (2.0 g, 12.34 mmol) was added. The mixture was cooled to 0° C., and benzyl chloroformate (1.76 mL, 12.34 mmol) was added. The mixture was stirred 5 min at 0° C., the cold bath removed, and then stirring was continued at room temperature overnight (˜16 hours). The mixture was evaporated, and partitioned with a 1:1 mixture of ethyl acetate and water. The organic layer was washed with water, and then brine. The organic layer was dried with Na₂SO₄, and evaporated to yield 320 (3.60 g, 99% yield) of suitable purity for use in subsequent reactions. Data for 320: ¹HNMR (300 MHz, CDCl₃): δ 7.18-7.14 (m, 5H), 7.42 (s, 1H), 6.98 (dd, J=11, 3 Hz, 1H), 6.48 (s, 1H), 5.06 (s, 2H).

Synthesis of Alcohol 321

Carbamate 320 (3.60 g, 12.16 mmol) was dissolved in 10 mL tetrahydrofuran, and the solution cooled to −78° C. n-Butyllithium (2.5 M in hexane, 7.6 mL, 12.16 mmol) was added slowly, and the mixture allowed to stir for 45 min at −78° C. R-(−)-Glycidyl butyrate (1.75 mL, 12.16 mmol) was added, and the mixture was stirred for 1 h at −78° C. The bath was removed and the reaction allowed to stir overnight at room temperature. The reaction was quenched with 25 mL saturated ammonium chloride solution, and partitioned with ethyl acetate and water. The aqueous layer was extracted thrice with ethyl acetate, and the combined organic layer was washed with brine, dried (Na₂SO₄), and evaporated to yield 321 (2.80 g, 88% yield) of suitable purity for use in subsequent reactions. Data for 321: ¹HNMR (300 MHz, CDCl₃): δ 7.59 (s, 1H), 7.33 (s, 1H), 4.68 (m, 1H), 3.91 (m, 3H), 3.67 (dd, J=16, 4 Hz, 1H).

Synthesis of Azide 323

Alcohol 321 (2.80 g, 10.68 mmol) was dissolved in 10 mL methylene chloride, and the mixture cooled to 0° C. Triethylamine (3.0 mL, 21.37 mmol) was added, followed by methanesulfonyl chloride (1.15 mL, 15.0 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. Methylene chloride (20 mL) was added, and the mixture washed twice with 1N HCl, then twice with 10% aqueous sodium carbonate, and then brine. The organic phase was dried (Na₂SO₄), and evaporated to yield mesylate 322 (3.60 g, 99% yield). Data for 322: ¹HNMR (300 MHz, CDCl₃): δ 7.67 (s, 1H), 7.42 (s, 2H), 4.94 (m, 1H), 4.47 (m, 2H), 4.26 (m, 1H), 4.0 (m, 1H), 3.03 (s, 3H).

A solution of mesylate 322 (3.60 g, 10.58 mmol) in dimethylformamide (10 mL) was treated with sodium azide (2.6 g, 40.21 mmol) and the mixture heated to 80° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 323 (2.53 g, 84% yield) as a yellow solid of suitable purity for use in subsequent reactions. Data for 323: ¹HNMR (300 MHz, CDCl₃): δ 7.61 (s, 1H), 7.30 (s, 2H), 4.75 (m, 1H), 4.01 (m, 1H), 3.75 (m, 1H), 3.66 (dd, J=17, 4 Hz, 1H), 3.51 (dd, J=4, 17 Hz, 1H).

Synthesis of Triazole 225

A solution of alkyne 173 (170 mg, 0.220 mmol) in tetrahydrofuran (10 mL) was treated with azide 323 (100 mg, 0.320 mmol), N,N-diisopropylethylamine (0.05 mL, 0.22 mmol) and copper (I) iodide (0.03 g, 0.160 mmol), and the mixture was stirred under argon at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried and evaporated. The residue was purified by preparative thin layer chromatography using (80% CH₂Cl₂, 20% MeOH, 1% NH₄OH) to provide triazole 225 (180 mg, 77% yield) as a white solid. Data for 225: MS (ESI) m/z 1075 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.95 (s, 1H), 7.46 (s, 1H), 7.20 (d, J=8 Hz, 1H), 7.04 (s, 2H), 5.04-4.93 (m, 1H), 4.91 (s, 2H), 4.28 (d, J=6 Hz, 1H), 3.98-3.92 (m, 2H), 3.61 (s, 1H), 3.59-3.48 (m, 1H), 3.34 (s, 1H), 3.19 (s, 1H), 3.06 (m, 1H), 2.94 (m, 1H).

Synthesis of Triazoles 226 and 227

These compounds were synthesized from the requisite anilines using the procedures described above for the synthesis of triazole 225.

Data for 226: ¹H-NMR (300 MHz, CDCl₃, partial): δ 8.01 (s, 1H), 7.60 (s, 1H), 7.02 (m, 1H), 6.77 (m, 1H), 4.98-4.68 (m, 1H), 4.37 (s, 2H), 4.13-4.04 (m, 2H), 3.89 (m, 1H), 3.26 (s, 1H), 2.84 (m, 2H), 2.66 (m, 2H).

Data for 227: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 7.00 (s, 1H), 6.82 (d, J=9 Hz, 1H), 6.64 (d, J=9 Hz, 1H), 5.02-4.89 (s, 1H), 4.53 (m, 2H), 4.34 (m, 2H), 3.19 (m, 1H), 2.96 (m, 1H), 2.93 (m, 2H), 2.86 (m, 2H).

Example 32 Synthesis of Triazole 228

Scheme 56 details the synthesis of triazole 228. 5-Aminoquinoline was converted to oxazolidinone alcohol 325 via carbamate 324. The alcohol of 325 was the transformed to azide 326, which was parlayed to triazole 228 via cycloaddition with alkyne 173.

Synthesis of Azide 326

To a stirred 0° C. solution of 5-aminoquinoline (1.0 g, 6.9 mmol) in 2:1 acetone/water (15 mL) was added NaHCO₃ (1.0 g, 13.7 mmol) followed by benzyl chloroformate (1.1 mL, 7.7 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h then cooled to 0° C. and filtered. The filtrate was washed with water and ether and dried in a vacuum oven at 40° C. overnight. The yellow solid (carbamate 324) thus obtained (1.9 g, 100% yield) was used as-is without further purification.

To a mixture of 324 (1.9 g, 6.9 mmol) in 25 mL THF at −78° C. was added 4.3 mL (6.9 mmol) of 1.6M n-butyllithium-hexane over 5 minutes. After 30 minutes, 1 mL of (R)-glycidyl butyrate was added and the mixture allowed to stir at −78° C. for 1 hour and then at room temperature for 16 hr. Saturated ammonium chloride was added (25 mL) followed by ethyl acetate (100 mL). The layers were separated and the aqueous layer extracted with ethyl acetate

(3×50 mL). The combined organic extracts were dried on MgSO₄, filtered and concentrated to provide 2.3 g of yellow solid which was purified by silica gel chromatography (50 mm×6″ column, eluted with 1:1 hexane/EtOAc to afford alcohol 325 as a yellow solid (450 mg, 27% yield).

To a stirred solution of 325 (300 mg, 1.2 mmol) in DMF (5 mL) was added triethylamine (0.34 mL, 2.4 mmol) followed by methanesulfonyl chloride (95 μL, 1.2 mmol). The mixture was stirred at room temperature and for 2 h, and then sodium azide (1 g, 15 mmol) was added and the slurry stirred overnight. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried (Na₂SO₄), filtered and concentrated to give 287 mg of azide 326 as an off-white solid which was used without further purification.

Synthesis of Triazole 228

To a stirred solution of alkyne 173 (50 mg, 64 μmol) in THF (250 μL) was added azide

326 (18 mg, 67 μmol) and cuprous iodide (5 mg, 26 μmol). The resulting mixture was degassed by alternately applying vacuum and purging with argon gas. The mixture was stirred under argon at ambient temperature for 16 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 100:3 CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct 228 as a white solid (50 mg, 74% yield). Data for 228: MS (ESI) m/z 322.9 (M+3H)³⁺, 528.6 (M+2H)²⁺, 1056.4 (M+H)⁺, 1078.3 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 9.05 (d, J=3 Hz, 1H), 8.05 (m, 2H), 7.90 (bs, 1H), 7.71 (dd, J=8, 3 Hz, 1H), 7.48 (s, 1H), 7.50 (d, J=7.0 Hz, 1H), 5.18-5.01 (m, 1H), 4.95 (d, J=5 Hz, 1H), 4.75 (d, J=4 Hz, 2H), 4.58 (dd, J=10, 2 Hz, 1H), 4.38 (d, J=7 Hz, 1H), 4.25 (t, J=9 Hz, 1H), 4.06 (dd, J=9, 6 Hz, 1H), 4.08-3.92 (m, 1H), 3.79 (d, J=7 Hz, 1H), 3.26 (s, 3H), 3.15 (dd, J=10, 7 Hz, 1H), 2.95 (t, J=10 Hz, 1H), 2.28 (s, 3H), 2.20 (s, 3H), 0.82 (m, 6H).

Example 33 Synthesis of Triazoles 229-232

Scheme 57 details the synthesis of targets 229-232. Hex-5-yn-1-ol was converted to tosylate 327 which served as an alkylating agent for amine 171. Acetylene 328 was the precursor for cycloaddition reactions with azides 326, 158, 189, and 188 to yield triazoles 229, 230, 231, and 232 respectively.

Synthesis of Tosylate 327

To a stirred, ice-cold solution of hex-5-yn-1-ol (1.0 g, 10.2 mmol) in ether (20 mL) was added p-toluenesulfonyl chloride (2.14 g, 11.2 mmol). Powdered KOH (1.1 g, 20.4 mmol) was then added portion-wise over 5 minutes. The slurry was stirred at 0° C. for 3 hours then poured into 100 mL water, and extracted with ether (2×50 mL). The combined organic extracts were washed with brine, dried over MgSO₄, filtered, and concentrated to afford 327 as a colorless oil (2.3 g, 89% yield). Data for 327: ¹HNMR (300 MHz, CDCl₃): δ 7.80 (d, J=8 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 4.05 (t, J=6 Hz, 2H) 2.45 (s, 3H), 2.19 (td, J=7, 3 Hz, 2H), 1.79 (pent, J=7 Hz, 2H), 1.55 (pent., J=7 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 144.8, 133.0, 129.9, 127.9, 83.4, 69.9, 69.0, 27.7, 24.2, 21.6, 17.7.

Synthesis of Alkyne 328

A 20 mL vial was charged with tosylate 327 (0.20 g, 0.85 mmol), N-desmethyl azithromycin 171 (0.5 g, 0.68 mmol), and Hunig's base (10 mL), and then purged with argon gas and sealed. The solution was stirred in a 100° C. oil bath for 6 h. After cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO₃ (50 mL) and extracted with CH₂Cl₂ (3×50 mL). The combined organic extracts were washed with brine, dried over K₂CO₃, filtered, and concentrated to afford 0.8 g of a white solid. Purification by silica gel flash chromatography (25 mm×6″ column eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH) gave 328 as a white solid (0.38 g, 68% yield). Data for 328: MS (ESI) m/z 408.0 (M+2H)²⁺,815.3 (M+H)⁺.

Synthesis of Triazole 229

To a stirred solution of alkyne 328 (50 mg, 63 μmol) in THF (250 μL) was added azide 326 (18 mg, 67 μmol) and cuprous iodide (5 mg, 26 μmol). The resulting mixture was degassed by alternately applying vacuum and purging with argon gas. The mixture was stirred under argon at ambient temperature for 16 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 100:3 CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct 229 as a white solid (54 mg, 76% yield). Data for 229: MS (ESI) m/z 332.2 (M+3H)³⁺, 542.5 (M+2H)²⁺, 1070.3 (M+H)⁺ 1092.2 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 9.10 (d, J=3 Hz, 1H), 8.05 (m, 2H), 8 (bs, 1H), 7.72 (dd, J=8, 3 Hz, 1H), 7.48 (s, 1H), 7.50 (d, J=7 Hz, 1H), 5.20-5.03 (m, 1H), 4.95 (d, J=5 Hz, 1H), 4.75 (d, J=4 Hz, 2H), 4.58 (dd, J=10, 2 Hz, 1H), 4.36 (d, J=7 Hz, 1H), 4.23 (t, J=9 Hz, 1H), 4.07 (dd, J=9, 6 Hz, 1H), 4.08-3.94 (m, 1H), 3.79 (d, J=7 Hz, 1H), 3.24 (s, 3H), 3.15 (dd, J=10, 7 Hz, 1H), 2.95 (t, J=10 Hz, 1H), 2.28 (s, 3H), 2.20 (s, 3H), 0.83 (m, 6H).

Synthesis of Triazole 230

To a stirred solution of 328 (35 mg, 43 μmol) in THF (150 μL) was added Hunig's base (30 μL), azide 158 (28 mg, 86 μmol), and cuprous iodide (4 mg, 21 μmol). The mixture was degassed by alternately applying vacuum and purging with argon gas. The slurry was stirred under argon at ambient temperature for 4 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford triazole 230 as a white solid (24 mg, 50% yield). Data for 230: MS (ESI) m/z 568.8 (M+2H)²⁺, 1136.4 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.45 (bs, 1H), 7.55 (s, 1H), 7.33 (dd, J=14, 2 Hz, 1H), 6.98 (dd, J=9, 2 Hz, 1H), 6.90 (dd, J=14, 9 Hz, 1H), 5.10-4.95 (m, 2H), 4.80-4.60 (m, 2H), 4.50 (d, J=7 Hz 1H), 3.32 (s, 3H), 2.32 (bs, 3H), 2.22 (bs, 3H), 0.90 (m, 6H).

Synthesis of Triazole 231

To a stirred solution of 328 (35 mg, 43 μmol) in THF (150 μL) was added Hunig's base (30 μL), azide 189 (20 mg, 86 μmol) and cuprous iodide (4 mg, 22 μmol). The resulting slurry was degassed by alternately applying vacuum and purging with argon gas. The mixture was stirred under argon at ambient temperature for 4 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford the triazole adduct 231 as a white solid (31 mg, 70% yield). Data for 231: MS (ESI) m/z 526.4 (M+2H)²⁺, 1073.5 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.6 (bs, 1H), 7.55 (s, 1H), 7.4-7.2 (m, 2H), 7.08 (dd, J=8, 2 Hz, 1H), 6.78 (td, J=6, 2 Hz, 2H), 5.1-5.0 (m, 2H), 4.8-4.6 (m, 3H), 4.4 (d, J=7 Hz, 1H), 3.95 (dd, J=9, 6 Hz, 1H), 3.31 (s, 3H), 2.32 (bs, 3H), 2.25 (s, 3H), 0.82 (m, 6H).

Synthesis of Triazole 232

To a stirred solution of 328 (50 mg, 62 μmol) in THF (150 μL) was added azide 188 (18 mg, 65 μmol) and cuprous iodide (5 mg, 26 μmol). The resulting mixture was degassed by alternately applying vacuum and purging with argon gas. The mixture was stirred under argon at ambient temperature for 16 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct 232 as a white solid (54 mg, 81% yield). Data for 232: MS (ESI) m/z 538.4 (M+2H)²⁺, 1075.4 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.87 (dd, J=7, 2 Hz, 2H), 7.70 (bs, 1H), 7.45 (dd, J=9, 2 Hz, 2H), 4.90 (d, J=4 Hz, 1H), 4.75-4.60 (m, 2H), 4.58 (d, J=9 Hz, 1H), 4.39 (d, J=7 Hz, 1H), 4.20 (d, J=5 Hz, 1H), 4.18 (t, J=9 Hz, 1H), 4.10-3.90 (m, 1H), 3.92 (dd, J=10, 6 Hz, 1H), 3.32 (s, 3H), 3.15 (dd, J=10, 7 Hz, 1H), 2.95 (t, J=10 Hz, 1H), 2.28 (s, 3H), 2.20 (s, 3H), 0.82 (m, 6H).

Example 34 Synthesis of Triazoles 233 and 234 Synthesis of Triazole 233

Compound 180 (50 mg, 49 μmol) was dissolved in EtOH (1.6 mL), and 1N HCl (aq) was then added (0.4 mL) and the solution stirred at room temperature for 12 h. The reaction mixture was diluted with 10 mL aq. 0.2N HCl and washed with CH₂Cl₂ (3×10 mL). The aqueous layer was then adjusted to pH 10 by addition of 2N KOH and extracted with CH₂Cl₂ (2×10 μL). The latter two extracts were dried on K₂CO₃, filtered and concentrated to afford 233 as a solid (37 mg, 87% yield). Data for 233: MS (ESI) m/z 433.4 (M+2H)2⁺, 865.3 (M+H)⁺, 887.3 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.59 (s, 1H), 7.35-7.20 (m, 2H), 7.05 (dd, J=8, 2 Hz, 1H), 6.78 (td, J=8, 2 Hz, 2H), 4.98 (m, 1H), 4.75-4.60 (m, 3H), 4.35 (d, J=7 Hz, 1H), 4.15-3.98 (m, 2H), 3.88 (dd, J=9, 6 Hz, 1H), 3.7 (dd, J=10, 4 Hz, 1H), 2.31 (bs, 3H), 2.10 (s, 3H), 0.82 (m, 6H).

Synthesis of Triazole 234

Compound 231 (10 mg, 8.8 μmol) was dissolved in EtOH (0.8 mL), and 1N HCl (aq) was then added (0.2 mL) and the solution stirred at room temperature for 12 h. The reaction mixture was diluted with 10 mL aq. 0.2N HCl and washed with CH₂Cl₂ (3×10 mL). The aqueous layer was then adjusted to pH 10 by addition of 2N KOH and extracted with CH₂Cl₂ (2×10 mL). The latter two extracts were dried on K₂CO₃, filtered, and concentrated to afford 234 as a solid (7 mg, 89% yield). Data for 234: MS (ESI) m/z 447.2 (M+2H)²⁺, 893.5 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.59 (s, 1H) 7.35-7.20 (m, 2H), 7.00 (dd, J=8, 2 Hz, 1H), 6.78 (td, J=8, 2 Hz, 2H), 5.05-4.95 (m, 1H), 4.75-4.60 (m, 3H), 4.40 (d, J=7 Hz 1H), 4.15-3.98 (m, 2H), 3.88 (dd, J=9, 6 Hz, 1H), 3.70 (dd, J=10.4, 4.43 Hz, 1H), 2.31 (bs, 3H), 2.10 (s, 3H), 0.82 (m, 6H).

Example 35 Synthesis of Triazoles 235 and 236

Scheme 58 illustrates the synthesis of triazoles 235 and 236. 2-Penten-4-yn-1-ol was converted to tosylate 329 which was used to alkylate amine 171 to yield enyne 330. The cycloaddition of alkyne 330 with azide 158 and 189 gave triazole products 235 and 236 respectively.

Synthesis of Tosylate 329

To a stirred ice-cold solution of 2-penten-4-yn-1-ol (0.821 g, 10 mmol) in ether (25 mL) was added p-toluenesulfonyl chloride (2.0 g, 10.5 mmol). Powdered KOH (1.0 g, 17.8 mmol) was then added portionwise over 5 minutes. The slurry was stirred at 0° C. for 45 minutes. The reaction mixture was poured into 100 mL water, and extracted with ether (2×50 mL). The combined organic extracts were washed with brine, dried over MgSO₄, filtered, and concentrated to afford 329 as a yellow oil (2.1 g, 89% yield). Data for 329: ¹HNMR (300 MHz, CDCl₃): δ 7.80 (d, J=8 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 6.12 (dt, J=16, 6 Hz, 1H), 5.70 (ddd, J=16, 2, 2 Hz, 1H), 4.60-4.50 (m, 2H), 2.95 (d, J=2, Hz 1H), 2.45 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 145.1, 135.9, 132.9, 130.0, 127.9, 113.9, 80.3, 79.8, 69.0, 21.66.

Synthesis of Enyne 330

A 20 mL vial was charged with tosylate 329 (0.20 g, 0.85 mmol), N-desmethyl azithromycin 171 (0.5 g, 0.68 mmol), and Hunig's base (10 mL) then purged with argon gas and sealed. The solution was stirred in a 100° C. oil bath for 1 h. After cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO₃ (50 mL) and extracted with CH₂Cl₂ (3×50 mL). The combined organic extracts were washed with brine, dried over K₂CO₃, filtered, and concentrated to afford 0.72 g of a viscous yellow oil. Purification by silica gel flash chromatography (25 mm×6″ column eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH) gave 330 as a yellow solid (0.48 g, 88% yield). Data for 330: MS (ESI) m/z 400.2 (M+2H)²⁺, 799.3 (M+H)⁺, 821.2 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.00 (bs, 1H), 6.20 (dt, J=16, 7, Hz, 1H), 5.70-5.60 (m, 1H), 5.00 (d, J=4 Hz, 1H), 4.65 (m, 1H), 4.48 (d, J=7 Hz, 1H), 4.28 (dd, J=6, 2 Hz, 1H), 4.15-3.99 (m, 1H), 3.82 (d, J=6 Hz, 1H), 3.65 (d, J=7 Hz, 1H), 3.60-3.40 (m, 1H), 3.32 (s, 3H), 3.32-3.20 (m, 2H), 2.32 (s, 3H), 2.26 (s, 3H), 0.86 (m, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 179.3, 144.4, 111.8, 103.8, 96.2, 85.1, 82.6, 79.7, 79.0, 78.5, 77.5, 75.7, 75.3, 74.4, 73.8, 71.9, 71.0, 69.4, 66.5, 65.4, 62.9, 57.0, 50.39, 45.9, 43.4, 42.0, 37.6, 37.5, 35.9, 31.8, 31.2, 28.2, 27.7, 22.8, 22.5, 22.2, 22.0, 19.3, 17.1, 16.3, 12.1, 10.3, 8.6.

Synthesis of Triazole 235

To a stirred solution of 330 (20 mg, 25 μmol) in THF (100 μL) was added Hunig's base (20 EL), azide 158 (16 mg, 50 μmol), and cuprous iodide (2.4 mg, 13 μmol). The resulting mixture was degassed by alternately applying vacuum and purging with argon gas. The slurry was stirred under argon at ambient temperature for 4 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford triazole 235 as a white solid (14 mg, 50% yield). Data for 235: MS (ESI) m/z 560.8 (M+2H)²⁺, 1120.5 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.60 (bs, 1H), 7.62 (s, 1H), 7.40-7.20 (m, 1H), 7.00-6.78 (m, 2H), 6.55-6.20 (m, 2H), 5.10-4.90 (m, 2H), 4.50 (d, J=10 Hz 1H), 3.18 (s, 3H), 2.28 (bs, 3H), 2.16 (bs, 3H), 0.90 (m, 6H).

Synthesis of Triazole 236

To a stirred solution of 330 (20 mg, 25 μmol) in THF (100 μL) was added Hunig's base (20 μL), azide 189 (16 mg, 50 μmol), and cuprous iodide (2.4 mg, 13 μmol). The resulting mixture was degassed by alternately applying vacuum and purging with argon gas. The slurry was stirred under argon at ambient temperature for 4 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct 236 as a white solid (18 mg, 70% yield). Data for 236: MS (ESI) m/z 518.2 (M+2H)²⁺, 1035.2 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.70 (bs, 1H), 7.65 (s, 1H), 7.40-7.20 (m, 2H), 7.05 (dd, J=8, 2 Hz, 1H), 6.78 (td, J=8, 2 Hz, 2H), 6.60-6.20 (m, 2H), 5.10-4.90 (m, 2H), 4.40 (d, J=7 Hz 1H), 3.86 (dd, J=9, 7 Hz, 1H), 3.21 (s, 3H), 2.22 (bs, 3H), 2.16 (s, 3H), 0.82 (m, 6H).

Example 36 Synthesis of Triazoles 237-240

Scheme 59 illustrates the synthesis of triazoles 237-240. Propargyl alcohol was alkylated to afford silylether 331 and the silylether subsequently converted to tosylate 332. Alkylation of amine 171 with 332 afforded alkyne 333. Cycloaddition of 333 with azides 189 and 158 yielded triazoles 237 and 238 respectively. Hydrolysis of 237 and 238 provided triazoles 239 and 240.

Synthesis of Silylether 331

To a stirred slurry of sodium hydride (0.28 g, 6.97 mmol) in DMF (30 mL) was added propargyl alcohol (0.41 mL, 6.97 mmol) dropwise over 5 minutes. The mixture was stirred at room temperature for 45 min., then 2-[t-butyldimethylsiloxy]-bromoethane (1.8 mL, 8.4 mmol) was added in one portion. After 16 hours the reaction mixture was poured into water (100 mL) and extracted with 1:1 hexane/ether (3×50 mL). The combined organic extracts were washed with brine, dried on MgSO₄, filtered and concentrated in vacuo to afford 331 as a colorless oil which was used as-is without further purification (1.38 g, 92% yield).

Synthesis of Tosylate 332

Silylether 331 (0.86 g, 4 mmol) was dissolved in acetonitrile (20 mL) in a plastic culture tube and cooled to 0° C. Aqueous HF (48% w/w, 1 mL) was then added and the solution stirred at 0° C. for 3 hours. The reaction mixture was poured slowly into 100 mL saturated aqueous NaHCO₃ and extracted with ether (3×50 mL). The combined organic extracts were washed with brine, dried (K₂CO₃), filtered, and concentrated to afford a colorless oil (0.5 g). This oil was dissolved in anhydrous CH₂Cl₂ (5 mL), cooled to 0° C., and then Hunig's base was added (2 mL) followed by tosyl chloride (0.76 g, 4.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The solution was diluted with CH₂Cl₂ (50 mL) and washed with saturated aqueous NaHCO₃ and brine. The aqueous washes were back-extracted with CH₂Cl₂ (50 mL). The combined organic extracts were dried on MgSO₄, filtered, and concentrated to give 332 as a colorless oil (0.81 g, 80% yield). Data for 332: ¹HNMR (300 MHz, CDCl₃): δ 7.74 (m, 2H), 7.27 (m, 2H), 4.12 (t, J=5 Hz, 2H), 4.05 (d, J=2 Hz, 2H), 3.66 (t, J=5 Hz, 2H), 2.38 (s, 3H), 2.34 (t, J=2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 144.8, 133.0, 129.8, 128.0, 78.9, 75.0, 68.8, 67.1, 58.4, 21.6.

Synthesis of Alkyne 333

A 20 mL vial was charged with tosylate 332 (0.20 g, 0.82 mmol), N-desmethyl azithromycin 171 (0.5 g, 0.68 mmol), and Hunig's base (10 mL) and then purged with argon gas and sealed. The solution was stirred in a 100° C. oil bath for 6 h. After cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO₃ (50 mL) and extracted with CH₂Cl₂ (3×50 mL). The combined organic extracts were washed with brine, dried over K₂CO₃, filtered, and concentrated to afford 0.65 g of an off-white solid. Purification by silica gel flash chromatography (25 mm×6″ column eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH) gave 333 as a white solid (0.22 g, 37% yield). Data for 333: MS (ESI) m/z 409.2 (M+2H)²⁺, 817.0 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.50 (bs, 1H), 4.87 (d, J=4 Hz, 1H), 4.55 (dd, J=10, 2 Hz, 1H), 4.35 (d, J=7 Hz, 1H), 4.20 (dd, J=7, 2 Hz, 1H), 4.06 (d, J=2 Hz, 2H), 4.05-3.90 (m, 1H), 3.57 (d, J=7 Hz, 1H), 3.51 (t, J=6 Hz, 1H), 3.38 (d, J=6 Hz, 1H), 3.24 (s, 3H), 3.15 (dd, J=10, 7 Hz, 1H), 2.93 (t, J=10 Hz, 1H), 2.24 (s, 3H), 2.23 (s, 3H), 0.86 (m, 6H); ¹³C NMR (75 MHz,): δ 177.8, 106.84, 95.05, 82.3, 79.3, 76.0, 74.3, 73.1, 70.6, 69.9, 69.5, 65.8, 62.35, 60.34, 52.1, 44.6, 41.9, 37.3, 36.5, 36.1, 29.6, 26.7, 25.8, 21.2, 20.8, 18.6, 16.1, 15.9, 14.2, 10.9, 7.8.

Synthesis of Triazole 237

To a stirred solution of 333 (50 mg, 61 μmol) in THF (150 μL) was added Hunig's base (30 μL), azide 189 (20 mg, 86 μmol), and cuprous iodide (6 mg, 33 μmol). The resulting mixture was degassed by alternately applying vacuum and purging with argon gas. The slurry was stirred under argon at ambient temperature for 4 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct 237 as a white solid (31 mg, 70% yield). Data for 237: MS (ESI) m/z 527.4 (M+2H)²⁺, 1075.4 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.10 (1's, 1H), 7.72 (s, 1H), 7.40-7.20 (m, 2H), 7.05 (dd, J=8, 2 Hz, 1H), 6.78 (td, J=6, 2 Hz, 2H), 5.10-4.90 (m, 2H), 4.80-4.60 (m, 4H), 4.40 (d, J=7 Hz, 1H), 4.22 (d, J=4 Hz, 1H), 4.09 (t, J=9 Hz, 1H), 4.10-3.95 (m, 1H), 3.89 (dd, J=9, 6 Hz, 1H), 3.34 (s, 3H), 3.16 (dd, J=10, 8 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 3H), 0.90 (m, 6H).

Synthesis of Triazole 238

To a stirred solution of 333 (35 mg, 43 μmol) in THF (1150 μL) was added Hunig's base (30 μL), azide 158 (28 mg, 86 μmol), and cuprous iodide (4 mg, 21 μmol). The mixture was degassed by alternately applying vacuum and purging with argon gas. The mixture was stirred under argon at ambient temperature for 4 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct as a white solid (24 mg, 50% yield). Data for 238: MS (ESI) m/z 569.9 (M+2H)²⁺, 1160.4 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.05 (1's, 1H), 7.80 (s, 1H), 7.33 (dd, J=14, 2 Hz, 1H), 7.05 (dd, J=9, 2 Hz, 1H), 6.88 (t, J=9 Hz, 1H), 5.18-5.00 (m, 2H), 4.80-4.60 (m, 4H), 4.50 (d, J=7 Hz 11H), 4.13 (t, J=9 Hz, 1H), 3.92 (dd, J=9, 6 Hz, 1H), 3.34 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H), 0.90 (m, 6H).

Synthesis of Triazole 239

Compound 237 (10 mg, 9.8 μmol) was dissolved in EtOH (0.8 mL) and 1N HCl (aq) was then added (0.2 mL) and the solution stirred at room temperature for 16 h. The reaction mixture was diluted with 10 mL aq. 0.2N HCl and washed with CH₂Cl₂ (3×10 mL). The aqueous layer was then adjusted to pH 10 by addition of 2N KOH and extracted with CH₂Cl₂ (2×10 mL). The latter two extracts were dried on K₂CO₃, filtered and concentrated to afford triazole 239 as a solid (7 mg, 80% yield). Data for 239: MS (ESI) m/z 448.3 (M+2H)⁺, 895.3 (M+H)⁺.

Synthesis of Triazole 240

Compound 238 (10 mg, 8.7 μmol) was dissolved in EtOH (1.6 mL) and 1N HCl (aq) was then added (0.4 mL) and the solution stirred at room temperature for 12 h. The reaction mixture was diluted with 10 mL aq. 0.2N HCl and washed with CH₂Cl₂ (3×10 mL). The aqueous layer was then adjusted to pH 10 by addition of 2N KOH and extracted with CH₂Cl₂ (2×10 mL). The latter two extracts were dried on K₂CO₃, filtered and concentrated to afford triazole 240 as a solid (6 mg, 87% yield). Data for 240: MS (ESI) m/z 434.4 (M+2H)²⁺, 867.2 (M+H)⁺, 889.3 (M+Na)⁺.

Example 37 Synthesis of Ketolides 237-240

Scheme 60 depicts the synthesis of triazoles 241 and 242. Alkyne 197 was protected as diacetate 334, and then 334 was treated with sodium hexamethyldisilylazide and carbonyldiimidazole to provide imidazole carbamate 335. Michael addition of ammonia to 335 was followed by closure of the amine group onto the imidazole carbamate to afford carbamate 336. Seleective hydrolysis of 336 afforded alcohol 337 which was subsequently oxidized with the Dess-Martin periodinane to yield ketolide 338. Deprotection of 338 gave alkyne 339, which was treated with azides 158 and 189 to provide triazoles 241 and 242 respectively.

Synthesis of Diacetate 334

Alkyne 197 (1.50 g, 1.90 mmol) was dissolved in 5 mL methylene chloride and the mixture cooled to 0° C. Dimethylaminopyridine (47 mg, 0.38 mmol) and triethylamine (0.8 mL, 5.7 mmol) were added, followed by acetic anhydride (0.54 mL, 5.7 mmol). The mixture was allowed to warm to room temperature and stirred for 1.5 h. Methylene chloride (50 mL) was added and the mixture washed with sat. aqueous NaHCO₃, and then brine. The organic phase was dried (K₂CO₃) and evaporated to afford 1.9 g of a white solid. The crude solid was purified by silica gel flash chromatography (25 mm×6″ column eluted with 40:1 CH₂Cl₂/2N NH₃ in MeOH) to afford 334 as a white solid (1.4 g, 86% yield). Data for 334: MS (ESI) m/z 870.2 (M+H)⁺, 892.3 (M+Na)⁺.

Synthesis of Imidazole Carbamate 335

A solution of 334 (0.8 g, 0.92 mmol) in 5.0 mL THF was cooled to −40° C., NaHMDS (1.2 mL of a 1.0 M THF soln.) was added dropwise to the stirred solution over 5 min., and the mixture was stirred at −40° C. for 40 min. A solution of carbonyldiimidazole (0.60 g, 3.7 mmol) in 8 mL of a 5:3 mixture of THF and DMF was then added over a period of 30 minutes by syringe-pump. Ten minutes after the addition was complete the cold bath was removed and the reaction mixture was allowed to warm to room temperature. After 16 h the reaction mixture was diluted with EtOAc (20 mL) and the washed with sat. aqueous NaHCO₃ and brine. The organic phase was dried (Na₂SO₄), filtered, and evaporated to afford 335 as an off-white solid which was used without further purification (0.92 g, 100% yield). Data for 335: MS (ESI) m/z 968.4 (M+Na)⁺.

Synthesis of Carbamate 336

A solution of 335 (0.94 g, 0.92 mmol) in acetonitrile (10 mL) was treated with 15% aqueous ammonia (2 mL) and the mixture stirred at room temperature for 40 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed with sat. aqueous NaHCO₃ and brine, the aqueous washes were back-extracted twice with 50 mL portions of EtOAc. The combined organic extracts were dried (Na₂SO₄) and evaporated to afford 1.3 g of an off-white solid. Purification by silica gel flash chromatography (25 mm×6″ column eluted with 1:3 acetone/hexanes) gave 260 mg of 336 (31% yield) along with 100 mg of its C-10 epimer and 450 mg of a mixture of the two. Data for 336: MS (ESI) m/z 895.2 (M+H)⁺, 917.3 (M+Na)⁺.

Synthesis of Alcohol 337

A solution of 336 (209 mg, 0.221 mmol) in 0.1 N aqueous HCl (5 mL) was stirred at room temperature for 8 h. The reaction mixture was neutralized with saturated aqueous NaHCO₃ (50 mL) and extracted with methylene chloride (3×25 mL). The combined organic extracts were washed with brine, dried (K₂CO₃), filtered, and evaporated to give 190 mg of a white solid. The crude product was chromatographed on silica gel using a 3:1 hexane/acetone as the eluant to provide 337 (145 mg, 94% yield) as a white solid. Data for 337: MS (ESI) m/z 695.2 (M+H)⁺, 717.1 (M+Na)⁺.

Synthesis of Ketolide 338

To a stirred solution of 337 (80 mg, 0.115 mmol) in methylene chloride at 0° C. was added Dess-Martin periodinane (59 mg, 0.138 mmol). The reaction mixture was stirred at ambient temperature for 12 hours then placed directly on a silica gel chromatography column and eluted with 3:1 hexane/acetone to afford ketolide 338 (62 mg, 78% yield) as a white solid. Data for 338: MS (ESI) m/z 693.1 (M+H)⁺, 715.3 (M+Na)⁺.

Synthesis of Alkyne 339

A methanol solution of 338 (62 mg, 0.090 mmol) was stirred at 50° C. for 16 h. The reaction mixture was concentrated in vacuo to give 339 as a white solid (55 mg, 94% yield) which was used without further purification. Data for 339: MS (ESI) m/z 651.2 (M+H)⁺, 673.1 (M+Na)⁺.

Synthesis of Triazole 241

To a stirred solution of 339 (20 mg, 31 μmol) in THF (310 μL) was added Hunig's base (26 μL), azide 158 (14.8 mg, 46 μmol), and cuprous iodide (5.8 mg, 31 μmol). The resulting mixture was stirred at ambient temperature for 4 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct 241 as a white solid (26 mg, 86% yield). Data for 241: MS (ESI) m/z 972.3 (M+H)⁺, 994.3 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.60 (s, 1H), 7.41 (dd, J=14, 2 Hz, 1H), 7.00-6.60 (m, 2H), 6.75 (bs, 1H), 5.72 (dd, J=10, 3 Hz 1H), 5.01-4.90 (m, 1H), 4.75-4.52 (m, 3H), 4.33-4.05 (m, 3H), 2.18 (s, 3H), 0.90 (t, J=7 Hz, 3H).

Synthesis of Triazole 242

To a stirred solution of 339 (18 mg, 28 μmol) in THF (310 μL) was added Hunig's base (24 μL), azide 189 (10 mg, 42 μmol) and cuprous iodide (5.3 mg, 28 μmol). The resulting mixture was stirred at ambient temperature for 4 h. The entire reaction mixture was then placed atop a silica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct 242 as a white solid (21 mg, 85% yield). Data for 242: MS (ESI) m/z 887.3 (M+H)⁺, 909.3 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.65 (s, 1H), 7.55-7.30 (m, 2H), 7.10 (dd, J=8, 2 Hz, 1H), 6.82-6.70 (m, 1H), 6.75 (bs, 1H), 5.70 (dd, J=10, 3 Hz 1H), 5.18-4.99 (m, 1H), 4.80-4.52 (m, 3H), 4.33-4.05 (m, 3H), 2.20 (bs, 3H), 0.90 (t, J=7 Hz, 3H).

Example 38 Synthesis of Isoxazolines 243-245

Scheme 61 depicts the synthesis of isoxazolines 243-245. Known hydroxyiminoyl chloride 340 (J. Med. Chem. 2003, 46, 284) was converted to isoxazoline alcohol 341. The alcohol group of 341 was transformed to the azide 342, an intermediate used in subsequent aromatic substitution chemistry with nucleophiles to produce azides 343, 344 and 345. Azide 345 was acylated to provide azide 346. The cycloaddition of azides 343, 344, and 346 with alkyne 173 yielded target isoxazolines 243, 245, and 244 respectively.

Synthesis of Alcohol 341

To a solution of allyl alcohol (15.6 mL, 0.23 mol) in 600 mL chloroform was added a 1 M solution of diethyl zinc in hexanes (276 mL, 0.276 mol) between −10° C. to 0° C. After stirring for 10 min, (+)-diisopropyl L-tartrate (9.68 mL, 45.9 mmol) was added and the solution was stirred at 0° C. for 1 h. Dioxane (24 mL, 0.282 mol) was added followed by hydroxyiminoyl chloride 340 (40 g, 0.209 mol) and the solution was stirred at −5° C. to 0° C. for 1½ h, then poured into 1 M citric acid/ice (400 mL) and extracted with dichloromethane (2×200 mL). The combined organic extract was washed with water (100 mL), brine (100 mL), dried (Na₂SO₄) and evaporated to a volume of 50 mL. 1-Chlorobutane (250 mL) was added and again the solution evaporated to a volume of 50 mL. The beige suspension was filtered, washed with 1-chlorobutane (2×10 mL) and dried to afford 14.5 g of alcohol 341. The remaining supernatant was evaporated and purified by flash-chromatography (eluant: hexanes-ethyl acetate 2:1) yielding and additional 22.0 g of alcohol 341. The combined portions of alcohol 341 were recrystallized from 120 mL 1-chlorobutane-hexanes 4:1, yielding pure alcohol 341 (31.1 g, 70% yield, ee: 95% as determined by Mosher ester). Data for 341: ¹HNMR (300 MHz, CDCl₃): δ 7.55-7.45 (m, 1H), 7.39-7.12 (m, 2H), 4.95-4.83 (m, 1H), 3.91 (dd, J=1, 2 Hz, 1H), 3.69 ((dd, J=1, 2 Hz, 1H), 3.40-3.21 (m, 2H), 2.20 (br s, 1H).

Synthesis of Azide 342

To a solution of 341 (3.0 g, 14.1 mmol) in 60 mL dichloromethane was added Et₃N (3.53 mL, 25.2 mmol) followed by MsCl (1.31 mL, 16.9 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, then poured into 30 mL water/ice and extracted with dichloromethane (2×50 mL). The combined organic extract was washed with water (2×30 mL), brine (30 mL), dried (Na₂SO₄) and evaporated. The residue was dissolved in 50 mL DMF, and NaN₃ (1.83 g., 28.1 mmol) was added and the mixture stirred at 80° C. for 2 h. The mixture was poured into 30 mL water/ice and extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with water (2×30 mL), brine (30 mL), dried (Na₂SO₄) and evaporated. The residual oil was crystallized with 20 mL 1-chlorobutane-hexanes 2:1, yielding azide 342 (3.0 g, 89%). Data for 342: ¹HNMR (300 MHz, CDCl₃): δ 7.50-7.41 (m, 1H), 7.35-7.05 (m, 2H), 4.92-4.81 (m, 1H), 3.51-3.05 (m, 4H).

Synthesis of Azide 343

A mixture of 342 (400 mg, 1.68 mmol) and K₂CO₃ (302 mg, 2.18 mmol) in 6 mL morpholine was stirred at 120° C. for 48 h, then poured into 20 mL water/ice and extracted with ethyl acetate (2×10 mL). The combined organic extract was washed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: hexanes-ethyl acetate 2:1) yielding azide 343 (320 mg, 63%). Data for 343: MS (ESI) m/z 306 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.38-7.23 (m, 2H), 6.80-6.78 (m, 1H), 4.90-4.75 (m, 1H), 3.83-3.75 (m, 4H), 3.48-3.25 (m, 4H), 3.18-3.02 (m, 4H).

Synthesis of Azide 344

To a solution of imidazole (214 mg, 3.15 mmol) in 5 mL DMF was added NaH (60% dispersion in paraffin oil, 100 mg, 2.52 mmol) at 0° C. After stirring the mixture for 30 min, the azide 342 (0.5 g, 2.1 mmol) was added. The mixture was stirred at room temperature overnight and then 60° C. for 2 h, and then poured into 40 mL water/ice and extracted with ethyl acetate (3×20 mL). The combined organic extract was washed with water (3×20 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate followed by ethyl acetate-MeOH 20:1) yielding azide 344 (390 mg, 65%). Data for 344: ¹HNMR (300 MHz, CDCl₃): δ 7.92 (s, 1H), 7.72-7.45 (m, 3H), 7.39-7.23 (m, 2H), 5.10-4.96 (m, 1H), 3.69-3.41 (m, 3H), 3.31-3.20 (m, 1H).

Synthesis of Azide 345

A mixture of azide 342 (1.0 g, 4.2 mmol), K₂CO₃ (755 mg, 5.5 mmol) and piperazine (15 g, 175 mmol) was dissolved in 9 mL DMF. The mixture was stirred at 120° C. for 3 h, then poured into 50 mL water/ice and extracted with ethyl acetate-isopropanol 95:5 (3×30 mL). The combined organic extract was washed with water (3×20 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-MeOH 3:1) yielding azide 345 (793 mg, 63%). Data for 345: ¹HNMR (300 MHz, CDCl₃): δ 7.52-7.39 (m, 2H), 7.08-6.95 (m, 1H), 5.05-4.92 (m, 1H), 3.63-3.41 (m, 3H), 3.33-3.10 (m, 9H), 1.85 (br s, 1H).

Synthesis of Azide 346

To a solution of azide 345 (300 mg, 0.99 mmol) in 6 ml dichloromethane-DMF 2:1 was added glycolic acid (97.8 mg, 1.29 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (284 mg, 1.48 mmol) and diisopropyl ethylamine (0.344 mL, 1.98 mmol) at 0° C. The solution was stirred at room temperature over the weekend and then poured into 20 mL 5% aqueous Na₂CO₃/ice and extracted with ethyl acetate (2×15 mL). The combined organic extract was washed with water (2×10 mL), 10 mL 1M aqueous HCl, water (2×10 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate) yielding azide 346 (51 mg, 15%). Data for 346: ¹HNMR (300 MHz, CDCl₃): δ 7.39-7.25 (m, 2H), 6.91-6.80 (m, 1H), 4.91-4.79 (m, 1H), 4.15 (s, 2H), 3.83-3.75 (m, 2H), 3.50-3.26 (m, 5H), 3.18-3.04 (m, 5H).

Synthesis of Isoxazoline 243

To a solution of alkyne 173 (100 mg, 0.127 mmol) in 4 mL acetonitrile was added azide

343 (39 mg, 0.127 mmol), 2,6-lutidine (0.0163 mL, 0.139 mmol) and CuI (24 mg, 0.127 mmol). The mixture was stirred overnight at room temperature, then poured into 10 mL 5% aqueous NH₃/ice and extracted with ethyl acetate (3×20 mL). The combined organic extract was washed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-MeOH 5:1) yielding 243 (71 mg, 51%). Data for 243: MS (ESI) m/z 1092 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.31-8.21 (br s, 1H), 7.51 (s, 1H), 7.31-7.12 (m, 2H), 6.81 (t, J=1 Hz, 1H), 5.05-4.90 (s, 1H), 4.65-3.90 (m, 5H), 3.81-3.74 (m, 2H).

Synthesis of Isoxazoline 244

To a solution of alkyne 173 (100 mg, 0.127 mmol) in 4 mL acetonitrile was added azide 346 (46 mg, 0.127 mmol), 2,6-lutidine (0.0163 mL, 0.139 mmol) and CuI (14.5 mg, 0.076 mmol). The mixture was stirred overnight at room temperature, then poured into 10 mL 5% aqueous NH₃/ice and extracted with ethyl acetate (3×20 mL). The combined organic extract was washed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-MeOH 5:1) yielding 244 (58 mg, 40%). Data for 244: MS (ESI) m/z 1049 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.54 (s, 1H), 7.31-7.13 (m, 2H), 7.85-7.72 (m, 1H), 5.10-4.95 (m, 1H).

Synthesis of Isoxazoline 245

To a solution of alkyne 173 (100 mg, 0.127 mmol) in 4 mL acetonitrile was added 344 (36.3 mg, 0.127 mmol), 2,6-lutidine (0.0163 mL, 0.139 mmol) and CuI (24 mg, 0.127 mmol). The mixture was stirred overnight at room temperature, then poured into 10 mL 5% aqueous NH₃/ice and extracted with ethyl acetate (3×20 mL). The combined organic extract was washed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-MeOH 5:1) yielding 245 (60 mg, 44%). Data for 245: MS (ESI) m/z 1073 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.8 (s, 1H), 7.50-7.30 (m, 3H), 7.21-7.14 (m, 3H), 5.19-4.95 (m, 2H), 4.68-3.90 (m, 7H).

Example 39 Synthesis of Isoxazolines 246-250

Scheme 62 depicts the synthesis of isoxazolines 246-250. Hydroxyiminoyl chloride 347 was converted to isoxazoline alcohol 348 as described in the literature (J. Med. Chem. 2003, 46, 284). The alcohol group of 348 was transformed to the azide 349, which was treated with alkyne 173 to afford isoxazoline 246. Azide 349 was coupled to substituted boronic acids to afford azides 354 and 355, which were treated with alkyne 173 to afford isoxazolines 248 and 249. Alcohol 348 was coupled to substituted boronic acids to provide alcohols 350 and 351, which were subsequently converted to azides 352 and 353. The cycloaddition of 352 and 353 with alkyne 173 gave isoxazolines 250 and 247 respectively.

Synthesis of Azide 349

To a solution of alcohol 348 (2.00 g, 7.81 mmol) in CH₂CH₂ (40 mL) at 0° C. was added Et₃N (2.20 mL, 15.6 mmol), followed by the dropwise addition of MsCl (911 μL, 11.7 mmol). The mixture was stirred at 0° C. for 30 min, then poured into 30 mL water/ice and extracted with Et₂O (50 mL×3). The combined organic extract was washed with water (50 mL×3), dried over MgSO₄, and evaporated to give 2.70 g of the intermediate mesylate of suitable purity to be used in the next step. The mesylate (2.70 g) was dissolved in DMF (30 mL), NaN₃ (2.10 g, 31.238 mmol) was added, and the mixture stirred at 80° C. for 2.5 h. The mixture was poured into water/ice (150 mL) and Et₂O (300 mL). The organic extract was washed with water (150 mL×3), dried over MgSO₄, and concentrated to afford azide 349 as a white crystalline solid (2.10 g, 96% yield). Data for 349: ¹HNMR (300 MHz, CDCl₃): δ 7.54 (s, 4H), 4.93 (dddd, J=10, 8, 5, 5 Hz, 1H), 3.56 (dd, J=13, 5 Hz, 1H), 3.45 (dd, J=13, 5 Hz, 1H), 3.42 (dd, J=17, 11 Hz, 1H), 3.21 (dd, J=17, 7 Hz, 1H).

Synthesis of Alcohol 350

A mixture of alcohol 348 (1.00 g, 3.91 mmol), 4-methylthiophenyl boronic acid (1.10 g, 5.86 mmol), palladium acetate (18 mg, 0.078 mmol), 2-(di-tert-butylphosphino)biphenyl (47 mg, 0.156 mmol) and KF (678 mg, 11.7 mmol) in THF (10 mL) at room temperature was degassed by bubbling argon through the mixture. The mixture was then stirred at room temperature for 15 h. The red suspension was poured into 10 mL sat. Na₂CO₃ and 100 ml water. The mixture was extracted with 15% isopropyl alcohol in CH₂CH₂ (200 mL×3). The combined organic layer was washed with water (100 mL×3), dried over MgSO₄, and evaporated to provide 350 (1.2 g, 100% yield). Data for 350: ¹HNMR (300 MHz, CDCl₃): δ 7.73 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 4.90 (dddd, J=13, 8, 5, 3 Hz, 1H), 3.90 (ddd, J=12, 6, 3 Hz, 1H), 3.71 (ddd, J=12, 8, 5 Hz, 1H), 3.43 (dd, J=17, 11 Hz, 1H), 3.32 (dd, J=17, 8 Hz, 2H), 2.53 (s, 3H), 1.90 (dd, J=8, 6 Hz, 1H).

Synthesis of Alcohol 351

Alcohol 351 was synthesized by the same procedure as reported for alcohol 350 using 3-cyanophenyl boronic acid (956 mg, 5.86 mmol). The mixture was extracted with CH₂CH₂ (100 mL×3). The residue was isolated by flash-chromatography on silica gel (2/100 MeOH/CH₂CH₂ as eluant), to afford alcohol 351 (1.0 g, 92% yield). Data for 351: ¹HNMR (300 MHz, CDCl₃): δ 7.90-7.77 (m, 4H), 7.69-7.54 (m, 4H), 4.92 (dddd, J=11, 8, 5, 3 Hz, 1H), 3.92 (ddd, J=12, 6, 3 Hz, 1H), 3.72 (ddd, J=12, 8, 5 Hz, 1H), 3.45 (dd, J=17, 11 Hz, 1H), 3.34 (dd, J=17, 8 Hz, 1H), 1.92 (dd, J=8, 6 Hz, 1H).

Synthesis of Azide 352

To a suspension of alcohol 350 (2.00 g, 6.68 mmol) in CH₂CH₂ (40 mL) at 0° C. was added Et₃N (1.90 mL, 13.4 mmol), and then MsCl (776 μL, 10.0 mmol) dropwise. The mixture was stirred at room temperature for 2 h and then refluxed for 3 h. The mixture was cooled to room temperature and EtOAc/Hexane (150 mL/50 mL) was added. The white solid was collected, washed with water (30 mL×3), and dried under vacuum to afford 2 g of crude mesylate. The crude mesylate obtained above (0.50 g, 1.33 mmol) was suspended in DMF (8 mL), NaN₃ (348 mg, 5.30 mmol) was added and the mixture stirred at 80° C. for 4 h. The mixture was poured into water/ice (50 mL), extracted by EtOAc (30 mL×4), dried over MgSO₄, the residue was isolated by chromatography on silica gel (40/60 EtOAc/hexane as eluant) to afford azide 352 (305 mg, 71% yield) as a white powder. Data for 352: ¹HNMR (300 MHz, CDCl₃): δ 7.73 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 4.94 (m, 1H), 3.55 (dd, J=13, 5 Hz, 1H), 3.48 (m, 2H), 3.25 (dd, J=17, 7 Hz, 1H), 2.97 (s, 3H).

Synthesis of Azide 353

To a solution of alcohol 351 (1.00 g, 3.59 mmol) in CH₂CH₂ (20 mL) at 0° C. was added Et₃N (1.00 mL, 7.19 mmol), followed by the dropwise addition of MsCl (419 μL, 5.39 mmol). The mixture was stirred at 0° C. for 30 min, and then at room temperature for 2 h. The mixture was poured into 100 mL water/ice and EtOAc/hexane 150 mL/50 mL). The combined organic extract was washed with water (100 mL×3), dried over MgSO₄, and evaporated to give 1.20 g of the crude mesylate which was used directly in the next step without further purification. The mesylate (1.20 g) was dissolved in DMF (20 mL), and NaN₃ (884 mg, 13.47 mmol) was added, and the mixture was stirred at 80° C. for 2.5 h. The mixture was poured into water/ice (150 mL) and EtOAc (250 mL). The organic extract was washed with water (100 mL×3), dried over MgSO₄, and evaporated. The residue was separated by chromatography on silica gel (30/70 EtOAc/hexane as eluant) to afford azide 353 (836 mg, 77% yield) as a white crystalline solid. Data for 353: ¹HNMR (300 MHz, CDCl₃): δ 7.90-7.77 (m, 4H), 7.69-7.50 (m, 4H), 4.97 (dddd, J=15, 7, 5, 5 Hz, 1H), 3.57 (dd, J=13, 5 Hz, 1H), 3.50 (m, 2H), 3.26 (dd, J=17, 7 Hz, 1H).

Synthesis of Azide 354

A mixture of azide 349 (300 mg, 1.07 mmol), 4-(hydroxymethyl)phenyl boronic acid (286 mg, 1.60 mmol), palladium acetate (5 mg, 0.021 mmol), 2-(di-tert-butylphosphino)biphenyl (13 mg, 0.043 mmol) and KF (188 mg, 3.20 mmol) in THF (4 mL) at was degassed by bubbling argon through the mixture. The mixture was then stirred at room temperature for 15 h. The red suspension was poured into 5 mL sat. Na₂CO₃ and 20 mL water. The mixture was extracted with 5% MeOH/CH₂CH₂ (200 mL). The combined organic layer was washed by water (100 mL×3), dried over MgSO₄, and evaporated. The residue was purified by chromatography on silica gel (1.5/100 MeOH/CH₂CH₂ as eluant) to afford azide 354 (220 mg, 67% yield). Data for 354: ¹HNMR (300 MHz, CDCl₃): δ 7.75 (d, J=8 Hz, 2H), 7.65 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.47 (d, J=8 Hz, 2H), 4.95 (dddd, J=10, 8, 5, 5 Hz, 1H), 4.76 (d, J=6 Hz, 2H), 3.55 (dd, J=13, 5 Hz, 1H), 3.50 (dd, J=17, 11 Hz, 2H), 3.25 (dd, J=17, 7 Hz, 1H), 1.71 (dd, J=5, 5 Hz, 1H).

Synthesis of Azide 355

A mixture of azide 349 (300 mg, 1.07 mmol), 4-cyanophenyl boronic acid (261 mg, 1.60 mmol), palladium acetate (5 mg, 0.021 mmol), 2-(di-tert-butylphosphino)biphenyl (13 mg, 0.043 mmol) and KF (188 mg, 3.20 mmol) in THF (4 mL) at room temperature was degassed by bubbling argon through the mixture. The mixture was then stirred at room temperature for 15 h. The red suspension was poured into 5 mL sat. Na₂CO₃ and 20 mL water. The mixture was extracted with CH₂CH₂ (50 mL×3). The combined organic layer was washed by water (100 mL×3), dried over MgSO₄, and evaporated. The residue was purified by chromatography on silica gel (30/70 EtOAc/hexane as eluant) to afford azide 355 (300 mg, 93% yield). Data for 355: ¹HNMR (300 MHz, CDCl₃): δ 7.83-7.63 (m, 8H), 4.97 (dddd, J=16, 7, 5, 5 Hz, 1H), 3.58 (dd, J=13, 5 Hz, 1H), 3.50 (dd, J=16, 10 Hz, 1H), 3.40 (dd, J=13, 5 Hz, 1H), 3.27 (dd, J=16, 7 Hz, 1H).

General Procedure for the Synthesis of Isoxazolines 246-250

To a mixture of alkyne 173 (100 mg, 0.127 mmol), the appropriate azide (0.140 mmol, 1.1 eq) in acetonitrile (4.0 mL) at room temperature under argon was added 2,6-lutidine (22 μL, 0.191 mmol, 1.1 eq), followed by the addition of copper (I) iodide (12 mg, 0.064 mmol). The mixture was stirred at room temperature for 1.5 to 6 h. After the reaction was complete, 1 mL 5% NH₄OH was added. The mixture was stirred at room temperature for 10 min. The acetonitrile was removed under vacuum. The aqueous phase was extracted with CH₂Cl₂ (30 mL×3), dried over Na₂SO₄, and evaporated. The residue was purified by chromatography on silica gel (20/80 to 30/70 MeOH/EtOAc) to provide isoxazolines 246 (116 mg, 85% yield), 247 (120 mg, 87% yield), 248 (120 mg, 87% yield), 249 (72 mg, 52% yield), and 250 (93 mg, 66% yield).

Data for 246: MS (ESI) m/z 1067.6 (M−H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.56 (s, 1H), 7.53 (d, J=9 Hz, 2H), 7.74 (d, J=9 Hz, 2H), 5.12 (br s, 1H), 4.71-4.52 (m, 4H), 4.43 (d, J=7 Hz, 1H), 4.29 (br s, 1H), 4.08 (m, 1H), 3.69-3.16 (m, 10H), 3.03 (dd, J=10, 10 Hz, 1H).

Data for 247: MS (ESI) m/z 1090.5 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.88 (s, 1H), 7.83 (d, J=8 Hz, 1H), 7.75-7.55 (m, 7H), 5.17 (br s, 1H), 5.09 (br s, 1H), 4.80-4.60 (m, 4H), 4.41 (d, J=7 Hz, 1H), 4.26 (br s, 1H), 4.09 (m, 1H), 3.68-3.18 (m, 10H).

Data for 248: MS (ESI) m/z 1090.3 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.77-7.60 (m, 9H), 5.17 (br s, 1H), 5.09 (br s, 1H), 4.71-4.55 (m, 4H), 4.41 (d, J=7 Hz, 1H), 4.26 (br s, 1H), 4.09 (m, 1H), 3.67-3.20 (m, 4H).

Data for 249: MS (ESI) m/z 1095.4 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.69-7.57 (m, 7H), 7.46 (d, J=8 Hz, 2H), 5.12 (d, J=4 Hz, 2H), 4.70-4.54 (m, 4H), 4.42 (d, J=7 Hz, 1H), 4.28 (br s, 1H), 4.08 (m, 1H), 3.69-3.20 (m, 10H).

Data for 250: MS (ESI) m/z 1111.4 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.68-7.50 (m, 7H), 7.35 (d, J=8 Hz, 2H), 5.12 (br s, 1H), 4.71-4.54 (m, 4H), 4.43 (d, J=8 Hz, 1H), 4.29 (br s, 1H), 4.07 (m, 1H), 3.69-3.20 (m, 10H), 3.03 (dd, J=10, 10 Hz, 1H).

Example 40 Synthesis of Isoxazolines 251 and 252

Scheme 63 depicts the synthesis of isoxazoline 251. Hydroxyiminoyl chloride 357 was made from the oxime (356) of 3,5-dichlorobenzaldehyde. The cycloaddition of 357 and allyl alcohol (via the intermediate nitrile oxide) afforded racemic isoxazoline alcohol 358. The alcohol was converted to azide 360 via the mesylate 359. The cycloaddition of 360 with alkyne 173 yielded isoxazoline 251 (as a diasteromeric mixture). Isoxazoline 252 was synthesized (also as a diastereomeric mixture) by carrying 3,5-difluorobenzaldehyde through the sequence of Scheme 63.

Synthesis of Oxime 356

A solution of 3,5-dichlorobenzaldehyde (2.0 g, 11.42 mmol) and hydroxylamine hydrochloride (0.87 g, 12.57 mmol) in ethanol (40 mL) and water (80 mL) was cooled to 4° C., and NaOH (50% (w/w), 2.3 mL) was added. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was then neutralized to pH 6.0, and partitioned with methylene chloride and water. The aqueous layer was extracted twice with methylene chloride, and the combined organic layer was washed with brine, dried (Na₂SO₄), and evaporated to yield 356 (2.15 g, 99% yield) as a white solid. Data for 356: ¹HNMR (300 MHz, CDCl₃): δ 8.11 (s, 1H), 7.45 (s, 1H), 7.34 (s, 1H).

Synthesis of hydroximinoyl chloride 357

To a solution of oxime 356 (2.15 g, 11.31 mmol) in dimethylformamide (10 mL) was added N-chlorosuccinimide (1.5 g, 11.31 mmol). The reaction mixture was warmed to 50° C. for 1 h. The reaction was then diluted with ethyl acetate (50 mL), and washed with brine, dried (Na₂SO₄), and evaporated to yield 357 (2.60 g, 100% yield). Data for 357: ¹HNMR (300 MHz, CDCl₃): δ 7.8 (s, 1H), 7.50 (s, 1H), 7.17 (s, 1H).

Synthesis of isoxazoline alcohol 358

To a solution of hydroximinoyl chloride 357 (1.50 g, 6.68 mmol) in methylene chloride (50 mL) was added allyl alcohol (0.45 mL, 6.68 mmol). The mixture was cooled to 0° C., and triethylamine (1.0 mL, 6.68 mmol) was added. The reaction mixture was slowly warmed to room temperature, stirred for 16 h, quenched with water (50 mL), and extracted twice with methylene chloride. The combined organic layer was washed with brine, dried over Na₂SO₄, and evaporated to yield 358 (1.60 g, 100% yield). Data for 358: ¹HNMR (300 MHz, CDCl₃): δ 7.47 (s, 2H), 7.32 (s, 1H), 4.84 (m, 1H), 3.82 (dd, J=15, 3 Hz, 1H), 3.62 (dd, J=16, 4 Hz, 1H), 3.23 (m, 2H).

Synthesis of Mesylate 359

Alcohol 358 (1.60 g, 6.50 mmol) was dissolved in 5 mL methylene chloride, and the mixture cooled to 0° C. Triethylamine (1.8 mL, 13.0 mmol) was added, followed by methanesulfonyl chloride (0.7 mL, 9.10 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. Methylene chloride (20 mL) was added, and the mixture washed twice with 1N HCl, then twice with 10% aqueous sodium carbonate, and then brine. The organic phase was dried (Na₂SO₄), and evaporated to yield mesylate 359 (1.60 g, 99% yield). Data for 359: ¹HNMR (300 MHz, CDCl₃): δ 7.67 (s, 2H), 7.56 (s, 1H), 5.22 (m, 1H), 4.51 (m, 2H), 3.60 (m, 1H), 3.40 (dd, J=7, 15 Hz, 1H), 3.25 (s, 3H).

Synthesis of Azide 360

A solution of mesylate 359 (1.60 g, 6.15 mmol) in dimethylformamide (10 mL) was treated with sodium azide (1.6 g, 24.60 mmol) and the mixture heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 360 (1.28, 77% yield) as a yellow oil of suitable purity for use in subsequent reactions. Data for 360: ¹HNMR (300 MHz, CDCl₃): δ 7.45 (s, 2H), 7.39 (s, 1H), 3.51 (dd, J=17, 4 Hz, 1H), 3.35-3.20 (m, 2H), 3.13 (m, 1H).

Synthesis of Isoxazoline 251

A solution of alkyne 173 (170 mg, 0.220 mmol) in tetrahydrofuran (10 mL) was treated with azide 360 (0.08 g, 0.324 mmol), N,N-diisopropylethylamine (0.05 mL, 0.22 mmol) and copper (I) iodide (0.03 g, 0.160 mmol), and the mixture was stirred under argon at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried and evaporated. The residue was purified by preparative thin layer chromatography (using 80% CH₂Cl₂, 20% MeOH, 1% NH₄OH as eluant) to provide isoxazoline 251 (197 mg, 86% yield) as a yellow solid. Data for 251: ¹HNMR (300 MHz, CDCl₃, partial): δ 7.36 (s, 2H), 7.22 (s, 1H), 4.96 (m, 2H), 4.24 (m, 2H), 4.10 (m, 1H), 3.52-3.15 (m, 2H), 3.06 (s, 1H), 2.59 (m, 2H).

Synthesis of Isoxazoline 252

This compound was made from alkyne 173 and the requisite 3,5-difluoro azide using the same procedures reported above for the synthesis of isoxazoline 251. Data for 252: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 7.10 (d, J=3 Hz, 2H), 6.86 (m, 1H), 5.10 (m, 1H), 5.08 (m, 1H), 4.66 (m, 1H), 4.61 (m, 2H), 4.41 (m, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 3.68 (m, 2H), 3.32-3.22 (m, 2H), 2.84 (t, 2H).

Example 41 Synthesis of Triazoles 361-367

Scheme 64 depicts the synthesis of triazoles 361 and 362. Azide 416 was treated with alkynes 173 and 174 to produce triazoles 361 and 362 respectively.

Synthesis of Azide 416

Azide 416 was synthesized from 2-amino-3-methyl-thiazole using the chemistry reported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673). Data for 416: ¹HNMR (300 MHz, CDCl₃): δ 6.59 (s, 1H), 4.92-4.87 (m, 1H), 4.34 (t, J=9 Hz, 1H), 4.12 (dd, J=6, 3 Hz, 1H), 3.73 (dd, J=3, 12 Hz, 1H), 3.61 (dd, J=3, 12 Hz, 1H), 2.35 (s, 3H).

Synthesis of Triazole 361

To a mixture of alkyne 173 (150 mg, 0.191 mmol), azide 416 (55 mg, 0.229 mmol) and copper (I) iodide (18.3 mg, 0.096 mmol) was added THF (10 mL) and the mixture was repeatedly degassed and flushed with argon. Then i-Pr₂NEt (0.05 mL) was introduced and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into NH₄Cl (30 mL) and stirred for few minutes. Then NH₄OH (3 mL) was added and the mixture was extracted with methylene chloride (3×40 ml). The combined organic layer was dried (Na₂SO₄), concentrated and flash chromatographed over silica gel (methylene chloride: MeOH:NH₄OH=12:1:0.025) to provide 150 mg of the product. Data for 361: MS (ESI) m/z 514 (M+2H)₂ ⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.59 (s, 1H), 6.56 (s, 1H), 5.22-5.10 (m, 2H), 4.79-4.62 (m, 4H), 4.46-4.39 (m, 2H), 4.28 (br d, J=3 Hz, 1H), 0.91-0.87 (m, 6H).

Synthesis of Triazole 362

The cycloaddition of alkyne 174 (150 mg, 0.187 mmol) and azide 416 (49.2 mg, 0.206 mmol) was performed under similar conditions as described above for the synthesis of 361 to afford 169 mg of 362. Data for 362: MS (ESI) m/z 521 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.49 (s, 1H), 6.56 (s, 1H), 5.18-5.12 (m, 2H), 3.34 (s, 3H), 3.03 (t, J=9 Hz, 1H), 0.91-0.87 (m, 6H).

Synthesis of Triazole 363

Triazole 363 (117 mg) was synthesized from alkyne 174 (100 mg, 0.125 mmol) and azide 189 (29.7 mg, 0.126 mmol) following the same procedure as described above for compound 361. Data for 363: MS (ESI) m/z 519 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.52 (s, 1H), 7.35-7.28 (m, 2H), 7.08 (br d, J=8 Hz, 1H), 6.84 (dd, J=2, 8 Hz, 1H), 5.10-5.01 (m, 2H), 4.29 (d, J=3 Hz, 1H), 3.23 (t, J=8 Hz, 1H), 3.03 (t, J=9 Hz, 2H), 0.91-0.87 (m, 6H).

Synthesis of Triazole 364

Triazole 364 (141 mg) was synthesized from alkyne 174 (150 mg, 0.187 mmol) and azide 277 (57.5 mg, 0.206 mmol) following the same procedure as described above for compound 361. Data for 364: MS (ESI) m/z 541 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.52 (s, 1H), 7.22 (d, J=2 Hz, 1H), 6.93 (dd, J=2, 8 Hz, 1H), 6.83 (t, J=9 Hz, 1H), 5.09 (d, J=5 Hz, 1H), 5.05-4.98 (m, 1H), 4.45 (d, J=7 Hz, 1H), 3.88 (dd, J=6, 3 Hz, 1H), 3.34 (s, 3H), 3.03 (t, J=9 Hz, 1H), 0.91-0.87 (m, 6H).

Synthesis of Triazole 365

Triazole 365 (200 mg) was synthesized from alkyne 174 (150 mg, 0.187 mmol) and azide 266 (63.6 mg, 0.206 mmol) following the same procedure as described above for compound 361. Data for 365: MS (ESI) m/z 556 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.52 (s, 1H), 7.28-7.23 (m, 1H), 6.98-6.91 (m, 2H), 5.12 (d, J=5 Hz, 1H), 5.04-5.02 (m, 1H), 4.45 (d, J=7 Hz, 1H), 4.28 (br d, J=3 Hz, 1H), 4.13-4.05 (m, 2H), 3.88 (dd, J=6, 3 Hz, 1H), 3.74 (t, J=5 Hz, 2H), 3.34 (s, 3H), 3.03 (t, J=9 Hz, 1H), 0.91-0.87 (m, 6H).

Synthesis of Triazole 366

The required 3,5-difluorophenyl oxazolidinone azide was synthesized from 3,5-difluoroaniline using the same procedure as that used for the synthesis of azide 189. Triazole 366 (157 mg) was synthesized from alkyne 174 (150 mg, 0.187 mmol) and the 3,5-difluorophenyl oxazolidinone azide (52.3 mg, 0.206 mmol) following the same procedure as described above for compound 361. Data for 366: MS (ESI) m/z 528.6 (M+2H)²⁺, 1055.8 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 7.02 (dd, J=2, 9 Hz, 2H), 6.62-6.55 (m, 1H), 5.14 (d, J=5 Hz, 1H), 5.10-5.02 (m, 1H), 4.81 (d, J=6 Hz, 1H), 4.72 (d, J=4 Hz, 2H), 4.45 (d, J=7 Hz, 1H), 3.93 (dd, J=6, 3 Hz, 1H), 3.34 (s, 3H), 3.23 (dd, J=7, 3 Hz, 1H), 3.03 (t, J=10 Hz, 1H), 0.91-0.86 (m, 6H).

Synthesis of Triazole 367

Triazole 367 (200 mg) was synthesized from alkyne 174 (150 mg, 0.187 mmol) and azide 323 (59.1 mg, 0.206 mmol) following the same procedure as described above for compound 361. Data for 367: MS (ESI) m/z 545 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.58 (d, J=3 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J=9 Hz, 1H), 7.28-7.24 (m, 1H), 5.14 (d, J=4 Hz, 1H), 5.10-5.02 (m, 1H), 4.44 (d, J=7 Hz, 1H), 4.29 (br d, J=2 Hz, 1H), 3.95 (dd, J=6, 3 Hz, 1H), 3.34 (s, 3H), 3.23 (dd, J=7, 3 Hz, 1H), 3.03 (t, J=9 Hz, 1H), 0.91-0.86 (m, 6H).

Example 42 Synthesis of Triazoles 368-370

Scheme 65 depicts the synthesis of triazoles 368-370. The required azides 420, 424, and 428 were synthesized using standard methods from the appropriate anilines. The cycloaddition of these azides with alkyne 173 afforded triazoles 368-370.

Synthesis of Azides 420, 424, 428

The azides were synthesized from the substituted anilines using the chemistry reported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673).

Data for 420: MS (ESI) m/z 291.9 (M+H+CH₃CN)⁺, ¹H-NMR, (300 MHz, CDCl₃): δ 7.31 (t, J=8 Hz, 1H), 6.96-6.91 (m, 2H), 4.76 (m, 1H), 4.01 (t, J=9 Hz, 1H), 3.73 (m, 1H), 3.63 (dd, J=13, 4 Hz, 1H), 3.50 (dd, J=14, 5 Hz, 1H), 2.31 (s, 3H).

Data for 424: ¹H-NMR, (300 MHz, CDCl₃): δ 7.28 (dd, J=12, 2 Hz, 1H), 7.08-7.00 (m, 2H), 4.71 (m, 1H), 3.98 (t, J=9 Hz, 1H), 3.74 (m, 1H), 3.63 (dd, J=13, 4 Hz, 1H), 3.50 (dd, J=14, 5 Hz, 1H), 2.16 (d, J=2 Hz, 3H).

Data for 428: ¹H-NMR, (300 MHz, CDCl₃) δ 7.29 (m, 1H), 7.19 (m, 1H), 6.92 (t, J=9 Hz, 1H), 4.69 (m, 1H), 3.98 (t, J=9 Hz, 1H), 3.75 (m, 1H), 3.62 (dd, J=13, 4 Hz, 1H), 3.50 (dd, J=13, 5 Hz, 1H), 2.21 (s, 3H).

Synthesis of Triazole 368

This compound was obtained from the reaction of alkyne 173 (0.115 g, 0.148 mmol) with azide 420 (0.048 g, 0.192 mmol) in the presence of CuI (0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.05 mL) at room temperature within 30 min. The reaction was poured into a mixture containing saturated NH₄Cl/NH₄OH (pH=9.5, 30 mL) and extracted with CH₂Cl₂ (3×30 mL). The combined organic layer was dried over Na₂SO₄ and the solvent evaporated. The crude was purified on silica gel eluting with CH₂Cl₂/MeOH/NH₄OH 18:1:0.05 to 15:1:0.05 to 12:1:0.05 to give 368 as a white solid (0.146 g, 95% yield). Data for 368: MS (ESI) m/z 1037.1 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.59 (s, 1H), 7.05 (t, J=8 Hz, 1H), 6.89-6.84 (m, 2H), 5.02 (m, 2H), 4.37 (d, J=7 Hz, 1H), 4.22 (d, J=2 Hz, 1H), 4.07 (m, 2H), 3.78 (m, 1H), 3.60 (m, 2H), 0.82 (m, 6H).

Synthesis of Triazole 369

This compound was obtained from the reaction of alkyne 173 (0.115 g, 0.148 mmol) with azide 424 (0.048 g, 0.192 mmol) in the presence of CuI (0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.02 mL) at room temperature within 30 min. The reaction was worked-up as described for the synthesis of 368 and purified on silica gel eluting with CHCl₃/MeOH/NH₄OH 15:1:0.05 to give 369 as a white solid (0.121 g, 79% yield). Data for 369: MS (ESI) m/z 1037.8 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.61 (s, 1H), 7.24 (m, 1H), 7.11 (t, J=8 Hz, 1H), 6.95 (m, 1H), 5.08 (d, J=4 Hz, 1H), 5.02 (m, 1H), 4.69 (m, 3H), 4.57 (m, 1H), 4.42 (d, J=7 Hz, 1H), 4.27 (d, J=3 Hz, 1H), 4.10 (m, 2H), 3.91 (m, 1H), 3.65 (m, 2H), 0.88 (m, 6H).

Synthesis of Triazole 370

This compound was obtained from the reaction of alkyne 173 (0.115 g, 0.148 mmol) with azide 428 (0.048 g, 0.192 mmol) in the presence of CuI (0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.02 mL) at room temperature within 30 min. The reaction was worked-up as described for the synthesis of 368 and purified on silica gel eluting with CHCl₃/MeOH/NH₄OH 15:1:0.05 to give 370 as a white solid (0.129 g, 84% yield). Data for 370: MS (ESI) m/z 1037.8 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.62 (s, 1H), 7.23-7.16 (m, 2H), 6.98 (t, J=9 Hz, 1H), 5.08-5.04 (m, 2H), 4.72 (m, 3H), 4.44 (d, J=7 Hz, 1H), 4.29 (m, 2H), 4.11 (m, 2H), 3.93 (m, 1H), 3.66 (m, 2H), 0.90 (m, 6H).

Example 43 Synthesis of Triazoles 371 and 372

Scheme 66 depicts the synthesis of triazoles 371 and 372. The silylethers 429 and 430 were synthesized from the available carboxylic acids, and were transformed into azides 435 and 436. The cycloaddition of 435 and 436 yielded triazoles 371 and 372 respectively.

Synthesis of silylethers 429 and 430

3-(4-Amino-phenyl)-propionic acid was reduced to the corresponding amino alcohol as described in the literature (Anhowry et al., J. Chem. Soc. Perkin Trans. I 1974, 191-192). The crude amino alcohol was sequentially protected with CBZ- and TBS-groups as described below for compound 437. The crude was purified on silica gel (eluting with EtOAc/Hexanes, 1:7) to give compound 429 as colorless oil (about 74% yield, three steps).

(4-Nitro-phenyl)-acetic acid was reduced to the nitro-alcohol as described in the literature (Anhowry et al., J. Chem. Soc. Perkin Trans. I 1974, 191-192). Catalytic hydrogenation afforded the corresponding amino alcohol. Subsequent CBZ- and TBS-group protection, as described below for compound 437, followed by purification on a silica gel column (eluting with EtOAc/Hexanes, 1:8 to 1:7) gave compound 430 as white solid (about 78% yield, 4 steps).

Synthesis of Azides 435 and 436

Silylethers 429 and 430 were converted to azides 435 and 436 using the chemistry reported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673), followed by desilylation using standard conditions.

Synthesis of Triazoles 371 and 372

Triazole 371 was obtained from the reaction of alkyne 173 (0.120 g, 0.154 mmol) with azide 435 (0.051 g, 0.185 mmol) in the presence of CuI (0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.02 mL) at room temperature within 30 min. The reaction was worked-up as described for the synthesis of triazole 368 and purified on silica gel (eluting with CH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 14:1:0.05) to give 371 as a white solid (0.124 g, 76% yield). Data for 371: MS (ESI) m/z 1063.9 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.63 (s, 1H), 7.32 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 5.05 (m, 2H), 4.72 (m, 3H), 4.45 (d, J=7 Hz, 2H), 4.28 (d, J=4 Hz, 1H), 4.15 (m, 2H), 3.92 (m, 1H), 0.90 (m, 6H).

Triazole 372 was obtained from the reaction of alkyne 173 (0.120 g, 0.154 mmol) with azide 436 (0.049 g, 0.185 mmol) in the presence of CuI (0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.02 mL) at room temperature within 30 min. The reaction was worked-up as described for the synthesis of triazole 368 and purified on silica gel (eluting with CH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 14:1:0.05) to give 372 as a white solid (0.116 g, 72% yield). Data for 372: MS (ESI) m/z 1050.0 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.59 (s, 1H), 7.31 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 2H), 5.02 (m, 2H), 4.66 (m, 3H), 4.51 (m, 1H), 4.40 (d, J=6 Hz, 2H), 4.24 (m, 1H), 4.10 (m, 2H), 3.61 (m, 2H), 0.86 (m, 6H).

Example 44 Synthesis of Triazole 373

Scheme 67 depicts the synthesis of triazole 373. Trans 4-aminocyclohexanol was converted to carbamate 437 prior to further manipulation into azide 439. The cycloaddition of 439 with alkyne 173 afforded triazole 373.

Synthesis of Carbamate 437

Trans 4-aminocyclohexanol was protected with a CBZ-group as described in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673) and protected with a TBS-group as described in the literature (Green, T. W.; Wuts, P. G. M., Protective Groups in Organic Synthesis, 1991, John Wiley & Sons, Inc., pp 77-83) to give crude compound 437 which was used without further purification.

Synthesis of Azide 439

Carbamate 437 was converted to azide 439 using the chemistry reported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673).

Synthesis of Triazole 373

Triazole 373 was obtained from the reaction of alkyne 173 (0.140 g, 0.180 mmol) with azide 439 (0.050 g, 0.210 mmol) in the presence of CuI (0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.05 mL) at room temperature within 30 min. The reaction was worked-up as described for the synthesis of triazole 368 and purified on silica gel (eluting with CH₂Cl₂/MeOH/NH₄OH 14:1:0.075) to give triazole 373 as a white solid (0.135 g, 73% yield). Data for 373: MS (ESI) m/z 1027.8 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 5.13 (m, 2H), 4.90 (m, 2H), 4.61 (m, 4H), 4.12 (m, 3H), 0.90 (m, 6H).

Example 45 Synthesis of Triazoles 374-377

Scheme 68 depicts the synthesis of triazoles 374-377. The cycloaddition of fluoroaryl azides 440 and 441 with alkynes 173 and 174 provided triazoles 374-377.

Synthesis of Azides 440 and 441

The azides were synthesized from the substituted anilines using the chemistry reported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673).

Synthesis of Triazole 374

This compound was obtained from the reaction of alkyne 173 (0.250 g, 0.318 mmol) with azide 440 (0.090 g, 0.381 mmol) in the presence of CuI (0.031 g, 0.150 mmol) in THF (10 mL) and Hunig's base (0.1 mL) at room temperature within 30 min. The reaction was worked-up as described for the synthesis of 368 and purified on silica gel eluting with CH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to give 374 as a white solid (0.294 g, 90% yield). Data for 374: MS (ESI) m/z 1023.7 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.55 (s, 1H), 7.30 (m, 2H), 6.97 (t, J=9 Hz, 2H), 4.99 (m, 2H), 4.36 (d, J=7 Hz, 1H), 4.22 (d, J=3 Hz, 1H), 4.07 (m, 2H), 3.84 (m, 1H), 3.59 (m, 2H), 0.82 (m, 6H).

Synthesis of Triazole 375

This compound was obtained from the reaction of alkyne 174 (0.150 g, 0.187 mmol) with azide 440 (0.068 g, 0.288 mmol) in the presence of CuI (0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.05 mL) at room temperature within 30 min. The reaction was worked-up as described for the synthesis of 368 and purified on silica gel eluting with CH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 12:1:0.05 to give 375 as a white solid (0.139 g, 72% yield). Data for 375: MS (ESI) m/z 1037.7 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃): δ 7.46 (s, 1H), 7.27 (m, 2H), 6.97 (m, 2H), 5.05 (d, J=5 Hz, 1H), 4.96 (m, 1H), 4.65 (m, 4H), 4.38 (d, J=7 Hz, 1H), 4.22 (d, J=3 Hz, 1H), 4.05 (m, 2H), 3.87 (m, 1H), 3.56 (m, 2H), 0.83 (m, 6H).

Synthesis of Triazole 376

This compound was obtained from the reaction of alkyne 173 (0.140 g, 0.180 mmol) with azide 441 (0.053 g, 0.210 mmol) in the presence of CuI (0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.05 mL) at room temperature within 30 min. The reaction was worked-up as described for the synthesis of 368 and purified on silica gel eluting with CH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 15:1:0.1 to give 376 as a white solid (0.183 g, 98% yield). Data for 376: MS (ESI) m/z 1041.7 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.61 (s, 1H), 7.48 (m, 1H), 7.13 (m, 1H), 7.00 (m, 1H), 5.07 (m, 2H), 4.72 (m, 3H), 4.43 (d, J=7 Hz, 1H), 4.29 (m, 2H), 4.14 (m, 2H), 3.85 (m, 1H), 3.66 (m, 2H), 0.88 (m, 6H).

Synthesis of Triazole 377

Alkyne 174 (150 mg, 0.187 mmol) and azide 441 (52.3 mg, 0.206 mmol) were treated with copper (I) iodide under similar conditions as reported above for the synthesis of triazole 361 to afford 170 mg of 377. Data for 377: MS (ESI) m/z 528.5 (M+2H)²⁺, 1055.7 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.51 (s, 1H), 7.49-7.42 (m, 1H), 7.14 (dd, J=9, 9 Hz, 1H), 6.99-6.96 (m, 1H), 5.13 (d, J=5 Hz, 1H), 5.07-5.02 (m, 1H), 4.44 (d, J=7 Hz, 1H), 3.95 (dd, J=6, 3 Hz, 1H), 3.48 (s, 3H), 3.34 (s, 3H), 3.03 (t, J=9 Hz, 1H), 0.92-0.87 (m, 6H).

Example 46 Synthesis of Triazole 378

Scheme 69 depicts the synthesis of triazole 378. The reductive amination reaction of 4-iodobenzylamine and quinoline-4-carboxaldehyde yielded amine 442 which was converted to the BOC derivative 443. Palladium-catalyzed conversion of iodide 443 to the corresponding pinacol boronate ester was followed by in situ Suzuki coupling with iodoaryl azide 253 to yield azide 444. The cycloaddition of 444 with alkyne 173 gave triazole 378.

Synthesis of Amine 442

A solution of 4-iodobenzylamine (0.93 g, 4.0 mmol) in methanol (10 mL) was treated with quinoline-4-carboxaldehyde (0.50 g, 3.2 mmol), acetic acid (0.2 mL) and sodium triacetoxyborohydride (1.7 g, 8.0 mmol), and the mixture was stirred under argon at 23° C. for 3 h. The reaction mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate (2×100 mL), dried (Na₂SO₄), and evaporated to provide iodide 442 (0.83 mg, 69% yield) as a yellow oil. Data for 442: MS (ESI) m/z 375 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 8.80 (d, J=5 Hz, 1H), 8.07 (d, J=8 Hz, 1H), 7.94 (d, J=8 Hz, 1H), 7.65-7.58 (m, 1H), 7.59 (d, J=8 Hz, 2H), 7.52-7.42 (m, 1H), 7.37 (d, J=5 Hz, 1H), 7.05 (d, J=8 Hz, 2H), 4.13 (s, 2H), 3.76 (s, 2H).

Synthesis of Iodide 443

A solution of iodide 442 (0.66 g, 1.8 mmol) in methylene chloride (15 mL) was treated with di-tert-butyl dicarbonate (0.42 mL, 3.2 mmol), and heated to reflux for 0.5 h. The reaction mixture was evaporated, and the residue purified by flash chromatography (SiO₂, 15-50% ethyl acetate/methylene chloride) to provide iodide 443 (0.72 g, 86% yield) as a colorless oil. Data for 443: MS (ESI) m/z 475 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 8.85 (d, J=4 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 7.98-7.82 (m, 1H), 7.72-7.66 (m, 1H), 7.61 (d, J=8 Hz, 2H), 7.54-7.48 (m, 1H), 7.16 (d, J=5 Hz, 1H), 6.98-6.85 (m, 2H), 4.88-4.80 (m, 2H), 4.43-4.29 (m, 2H), 1.49-1.42 (m, 9H).

Synthesis of Azide 444

A solution of iodide 443 (0.22 g, 0.46 mmol) in dioxane (2.5 mL) was treated with triethylamine (0.19 mL, 1.4 mmol), pinacol borane (0.090 mL, 0.61 mmol), and Pd(dppf)Cl₂ (10 mg, 0.012 mmol) and heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with ethanol (0.83 mL) and H₂O (0.83 mL), treated with potassium carbonate (0.19 g, 1.4 mmol), azide 253 (0.17 g, 0.46 mmol), and Pd(dppf)Cl₂ (10 mg, 0.012 mmol), and heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with methylene chloride (50 mL), washed with saturated aqueous sodium bicarbonate (2×50 mL), dried (Na₂SO₄), and evaporated. Flash chromatography (SiO₂, 50-100% ethyl acetate/methylene chloride) provided azide 444 (0.18 g, 67% yield) as a yellow oil. Data for 444:1 HNMR (300 MHz, CD₃OD/CDCl₃): δ 8.76 (d, J=5 Hz, 1H), 8.04-8.00 (m, 2H), 7.77-7.69 (m, 1H), 7.62-7.43 (m, 8H), 7.33-7.25 (m, 1H), 4.89-4.83 (m, 1H), 4.28 (s, 2H), 4.22-4.12 (m, 1H), 3.94 (s, 2H), 3.92-3.88 (m, 1H), 3.79-3.72 (m, 1H), 3.62-3.56 (m, 1H).

Synthesis of Triazole 378

A solution of azide 444 (0.090 g, 0.15 mmol) in dichloromethane (4.0 mL) was treated with trifluoroacetic acid (4.0 mL) and stirred at 23° C. for 1 h. The solvent was removed under reduced pressure, and the residue dissolved in chloroform (100 mL) and washed with 10% aqueous potassium carbonate (100 mL), dried (Na₂SO₄), and evaporated to provide 50 mg of deprotected amine as an orange solid.

A solution of this crude amine (0.0430 g, 0.089 mmol) and alkyne 173 (0.056 g, 0.071 mmol) in tetrahydrofuran (1.5 mL) was treated with N,N-diisopropylethylamine (0.015 mL, 0.089 mmol) and copper (I) iodide (2.0 mg, 0.0089 mmol) and stirred under argon at 23° C. for 1 h. The reaction mixture was diluted with saturated aqueous ammonium hydroxide (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic fractions were dried (Na₂SO₄) and evaporated, and the residue purified by preparative thin-layer chromatography (PTLC, SiO₂, ammonium hydroxide/methanol/ethyl acetate/dichloromethane 0.5:10:15:74.5) to provide 378 (44 mg, 48% yield) as a white powder. Data for 378: MS (ESI) m/z 1270 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.89 (d, J=5 Hz, 1H), 8.12 (d, J=9 Hz, 1H), 8.06 (d, J=8 Hz, 1H), 7.72-7.68 (m, 1H), 7.62 (s, 1H), 7.19-7.17 (m, 1H), 4.30 (s, 2H), 3.96 (s, 2H), 3.33 (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H), 0.88-0.86 (m, 6H).

Example 47 Synthesis of Triazole 379

Scheme 70 depicts the synthesis of triazole 379. Azide 300 was converted to hydroxyamidine 445 which was subsequently cyclized with triethylorthoformate to oxadiazole azide 446. The cycloaddition of 446 with alkyne 173 yielded triazole 379.

Synthesis of Azide 446

A solution of azide 300 (300 mg, 1.1 mmol) in ethanol (5.5 mL) was treated with potassium carbonate (152 mg, 1.1 mmol) and hydroxylamine hydrochloride (153 mg, 2.2 mmol) and refluxed for 3 h. The reaction was cooled to 23° C. and the solvent was evaporated in vacuo. The crude hydroxyamidine was added to triethylorthoformate (5.5 mL) and the reaction was refluxed for 2 h, cooled to 23° C. and stirred for 48 h, and then refluxed for 1 h. The reaction was then cooled to 23° C. and diluted with ethyl acetate (20 mL). The organic layer was washed with 1 M hydrochloric acid (20 mL). Drying (Na₂SO₄) and evaporation provided oxadiazole azide 446 (80 mg, 0.26 mmol, 24% yield). Data for 446: ¹HNMR (300 MHz, CDCl₃): δ 8.80 (s, 1H), 8.12 (t, J=8 Hz, 1H), 7.66 (dd, J=13, 2 Hz, 1H), 7.43 (dd, J=9, 2 Hz, 1H), 4.91-4.81 (m, 1H), 4.17-4.11 (m, 1H), 3.93 (dd, J=9, 6 Hz, 1H), 3.77 (dd, J=4, 13, 1H), 3.63 (dd, J=4, 13, 1H).

Synthesis of Triazole 379

A solution of alkyne 173 (135 mg, 0.17 mmol) and azide 446 (65 mg, 0.21 mmol) in tetrahydrofuran (1.3 mL) was treated with diisopropylethylamine (0.037 mL, 0.21 mmol) and then degassed by application of vacuum and introduction of argon. Copper (I) iodide (4 mg, 0.021 mmol) was added, and the reaction was again degassed. The reaction was stirred under argon at 23° C. for 1 h, and then purified by flash chromatography (SiO₂, ammonium hydroxide/methanol/dichloromethane (0.05:1:12)) to provide 379 (153 mg, 0.14 mmol, 82% yield) as a white powder. Data for 379: MS (ESI) m/z 1091.8 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.80 (s, 1H), 8.18-8.136 (m, 1H), 7.69 (s, 1H), 7.65 (dd, J=13, 2, 1H), 7.37-7.33 (m, 1H), 4.82-4.80 (m, 1H), 4.67 (dd, J=10, 2 Hz, 1H), 3.41 (s, 3H), 0.98-0.93 (m, 6H).

Example 48 Synthesis of Triazole 380

The required 3,5-difluoroaryl oxazolidinone azide was synthesized from 3,5-difluoroaniline using the chemistry reported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673).

Alkyne 328 (70 mg, 86 μmol), the above azide (33 mg, 129 μmol), and CuI (2 mg, 8 μmol) were reacted under the conditions described for the synthesis of triazole 228 to afford triazole 380 as a white solid (92.6 mg, 85 μmol). Data for 380: MS (ESI) m/z 543 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.99 (bs, 1H), 7.42 (s, 1H). 7.00-6.92 (m, 2H), 6.51 (tt, J=9, 2 Hz, 1H), 5.06-4.99 (m, 1H), 4.94 (d, J=6 Hz, 1H), 4.66 (d, J=5 Hz, 2H), 4.59 (dd, J=9, 2 Hz, 1H), 4.38 (d, J=7 Hz, 1H), 4.22 (dd, J=6, 2 Hz, 1H), 4.10 (t, J=8 Hz, 1H), 4.10-4.00 (m, 1H), 3.87-3.82 (m, 2H), 3.61-3.57 (m, 2H), 3.53-3.41 (m, 2H), 3.33 (s, 3H), 3.16 (dd, J=10, 4 Hz, 1H), 2.96 (t, J=10 Hz, 1H), 2.85-2.73 (m, 5H), 2.31 (s, 3H), 2.19 (s, 3H), 0.83 (d, J=6 Hz, 3H), 0.81 (t, J=7 Hz, 3H).

Example 49 Synthesis of Triazoles 381 and 382

Scheme 71 depicts the synthesis of triazoles 381 and 382. Amine 171 was converted to carbamate 447 prior to cycloaddition with azide 158 to afford triazole 381. Amine 171 was demethylated to yield amine 448, which was subsequently transformed to carbamate 449 and ultimately triazole 382.

Synthesis of Carbamate 447

To a stirred solution of 171 (0.72 g, 1.0 mmol) in CH₂Cl₂ (10 mL) and Hunig's base (1 mL), was added dropwise a CH₂Cl₂ solution of 4-butynyl chlorofomate (135 mg, 1.01 mmol in 2 mL). The mixture was stirred at rt for 16 h, then diluted to 50 mL with CH₂Cl₂ and washed with sat. aq. NaHCO₃ (50 mL) and brine (25 mL). The organic fraction was dried over K₂CO₃, filtered and concentrated to give 0.9 g of a foam which was purified by silica gel chromatography (25 mm×6″ column eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH) to afford carbamate 447 as a white solid (0.68 g, 0.83 mmol). Data for 447: MS (ESI) m/z 815 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.72 (bs, 1H), 5.07 (d, J=4 Hz, 1H), 4.95 (d, J=7 Hz, 1H), 3.32 (s, 3H), 2.90 (s, 3H), 2.31 (s, 3H), 1.34-1.27 (m, 8H), 1.27-1.15 (m, 10H), 1.10-0.99 (m, 9H), 0.92-0.84 (m, 6H).

Synthesis of Triazole 381

Alkyne 447 (60 mg, 72 μmol), azide 158 (35 mg, 108 μmol), and CuI (2 mg, 8 μmol) were reacted under the conditions described for the synthesis of compound 228 to afford triazole 381 as a white solid (67 mg, 65 μmol). Data for 381: MS (ESI) m/z 1137 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.9 (bs, 1H), 7.63 (s, 1H), 7.05-6.92 (m, 1H), 6.82 (t, J=9 Hz, 1H), 5.10-4.90 (m, 2H), 4.80-4.00 (m, 7H), 3.90-3.81 (m, 3H), 3.70-3.58 (m, 2H), 3.41-3.25 (m, 3H) 3.20 (pent, J=6, 1H), 3.10-2.96 (m, 4H), 2.92-2.38 (m 5H), 2.29 (s, 3H), 2.10-1.40 (m, 51H), 1.25-1.04 (m, 15H), 0.93 (d, J=8, 3H), 0.94-0.83 (m, 6H).

Synthesis of Amine 448

To a stirred solution of desmethyl azithromycin 171 (10.0 g, 13.6 mmol) in methanol (200 mL) was added sodium methoxide (1.33 g, 25 mmol). The mixture was cooled to 0° C. prior to the addition of iodine (3.55 g, 14 mmol). The mixture was stirred at 0° C. for 1.5 h, then warmed to rt over 1 h. The reaction mixture was poured into ice water (1 L) and the solution was adjusted to pH 12 by addition of KOH which led to the precipitation of a white solid. After sitting at 0° C. for 1 h, the solid was filtered to give 7.2 g of crude product which was recrystallized from boiling methanol to give 3.8 g of product as white crystals. Data for 448: MS (ESI) m/z 361.24 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.48 (bs, 1H), 5.18 (bs, 1H), 4.95 (d, J=4 Hz, 1H), 4.60 (dd, J=10, 2 Hz, 1H), 4.30 (d, J=8 Hz, 1H), 4.18 (dd, J=5, 2 Hz, 1H), 4.06-3.96 (m, 1H), 3.60-3.48 (m, 3H), 3.27 (s, 3H) 2.28 (s, 3H).

Synthesis of Carbamate 449

3′-N-bis-demethyl azithromycin 448 (180 mg, 0.25 mmol) was treated with 4-butynyl chlorofomate (35 mg, 0.25 mmol) under the same conditions described for the synthesis of 447 to afford carbamate 449 as a white solid (157 mg, 0.19 mmol). Data for 449: MS (ESI) m/z 1123 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.18 (bs, 1H), 4.92 (d, J=4 Hz, 1H), 4.78 (d, J=4 Hz, 1H), 4.39 (d, J=6 Hz, 1H), 4.15 (t, J=7 Hz, 2H), 4.05-3.92 (m, 1H), 3.28 (s, 3H), 2.30 (s, 3H), 1.68 (d, J=8 Hz, 1H), 1.51 (dd, J=8, 3 Hz, 1H), 1.28-1.12 (m, 8H), 1.27-1.15 (m, 10H), 1.05 (d, J=7 Hz, 3H), 1.00 (s, 3H), 0.91 (d, J=7 Hz, 3H), 0.92-0.84 (m, 6H).

Synthesis of Triazole 382

Alkyne 449 (40 mg, 49 μmol), azide 158 (24 mg, 73 μmol), and CuI (2 mg, 8 μmol) were reacted under the conditions described for the synthesis of compound 228 to afford triazole 382 as a white solid (67 mg, 65 μmol). Data for 382: MS (ESI) m/z 1135 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.30 (bs, 1H), 7.54 (s, 1H), 7.11-7.02 (m, 2H), 6.82-6.70 (m, 2H), 5.41 (d, J=5 Hz, 1H), 5.05-4.90 (m, 2H), 4.68 (d, J=4 Hz, 1H), 4.59 (d, J=6 Hz, 1H), 3.28 (s, 3H), 2.25 (s, 3H), 1.69 (d, J=8 Hz, 1H), 1.31-1.01 (m, 15H), 0.95 (d, J=8, 3H), 0.80 (t, J=8, 3H).

Example 50 Synthesis of Triazoles 383 and 384

Scheme 72 depicts the synthesis of triazoles 383 and 384. 4-Nitrobenzenesulfonyl chloride was convereted to sulfonamide 450 which was manipulated to carbamate 452 by standard chemistry. Oxazolidinone formation followed by azide formation gave 455. The cycloaddition of 455 with alkynes 173 and 174 rendered triazoles 383 and 384 respectively.

Synthesis of Azide 455

4-Nitrobenzenesulfonyl chloride (2.22 g, 10 mmol) was added to a solution of dimethylamine (10 mL, 2.0 M in THF, 20 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h and then at room temperature for additional 1 h. The THF was removed under vacuum, more water was added, and the precipitate was collected by filtration and dried to afford 450 (2.20 g, 96% yield). Data for 450: ¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 8.33 (d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 2H), 2.70 (s, 6H).

To a solution of sulfonamide 450 (2.2 g, 9.6 mmol) in methanol (30 mL) was added 10% Pd—C (0.25 g) and the resulting mixture was stirred at room temperature for 6 h under 1 atm hydrogen atmosphere. The Pd—C was removed by filtration on celite. The filtered solution was evaporated to provide 451 (1.8 g, 94% yield) as a white solid. Data for 451: ¹HNMR (300 MHz, CDCl₃): δ 7.43 (d, J=9 Hz, 2H), 6.59 (d, J=9 Hz, 2H), 2.53 (s, 6H).

Benzyl chloroformate (1.4 mL, 9.6 mmol) was added dropwise to a solution of aniline 451 (1.60 g, 8.0 mmol), and NaHCO₃ (2.70 g, 21 mmol) in a mixture of THF (5 mL) and water (3 mL) at 0° C. After stirring at 0° C. for 2 h and room temperature for 4 h, the reaction mixture was diluted with ethyl acetate (30 mL). The organic layer was washed with brine (3×50 mL), dried (MgSO₄) and concentrated to provide 2.35 g of white solid 452 in a yield of 93%. Data for 452: ¹HNMR (300 MHz, CDCl₃): δ 7.79 (d, J=9 Hz, 2H), 7.64 (d, J=9 Hz, 2H), 7.50-7.45 (m, 5H), 7.02 (br s, 1H), 5.30 (s, 2H), 2.76 (s, 6H).

To a solution of CBZ-protected amine 452 (1.0 g, 3 mmol) in THF (20 mL) was added n-BuLi (3.3 mL, 1.6 M in hexane, 5.28 mmol) at −78° C. and the mixture was stirred for 30 min. (R)-(−)-Glycidyl butyrate (0.53 mL, 3.75 mmol) was added, the reaction was stirred at −78° C. for 3 h and was then warmed to room temperature and stirred overnight. The reaction was carefully quenched with saturated NH₄Cl and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO₄) and concentrated. The crude product was recrystallized from ethyl acetate to give alcohol 453 as a white crystalline solid (0.45 g, 50% yield). Data for 453: MS (ESI) m/z 300.9 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.83 (d, J=9 Hz, 2H), 7.78 (d, J=9 Hz, 2H), 4.86 (m, 1H), 4.19-4.07 (m, 3H), 3.85 (dd, J=4, 13 Hz, 1H), 2.75 (s, 6H).

To a solution of alcohol 453 (200 mg, 0.67 mmol) and Et₃N (101 mg, 1.0 mmol) in CH₂Cl₂ (5 mL) was added methanesulfonyl chloride (92 mg, 0.80 mmol) at 0° C. The mixture was stirred at room temperature for 30 min. The CH₂Cl₂ solution was washed with brine, dried (MgSO₄), concentrated and crystallized from EtOAc to afford mesylate 454 (238 mg, 94% yield). Data for 454: MS (ESI) m/z 378.9 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.80 (d, J=9 Hz, 2H), 7.73 (d, J=9 Hz, 2H), 4.98 (m, 1H), 4.54 (dd, J=4, 12 Hz, 1H), 4.46 (dd, J=4, 12 Hz, 1H), 4.23 (t, J=9 Hz, 1H), 4.04 (dd, J=6, 9 Hz, 1H), 3.11 (s, 3H), 2.70 (s, 6H).

A mixture of 454 (200 mg, 0.52 mmol) and sodium azide (137 mg, 2.11 mmol) in DMF (4 mL) was heated at 80° C. for 3 h. The reaction mixture was diluted with EtOAc, washed with brine, dried (MgSO₄), concentrated and crystallized from EtOAc/MeOH to afford azide 455 (149 mg, 88% yield). Data for 455: ¹HNMR (300 MHz, DMSO): δ 7.72 (d, J=9 Hz, 2H), 7.67 (d, J=9 Hz, 2H), 4.83 (m, 1H), 4.11 (t, J=9 Hz, 1H), 3.77-3.58 (m, 3H), 2.58 (s, 6H).

Synthesis of Triazole 383

A mixture of alkyne 173 (118 mg, 0.15 mmol), azide 455 (54 mg, 0.165 mmol) and copper (I) iodide (28.5 mg, 0.15 mmol) in THF (5 mL) was repeatedly degassed and flushed with argon. Hunig's base (0.26 mL) was introduced and the mixture stirred at room temperature for 12 h. The reaction mixture was poured into saturated NH₄Cl (30 mL) and stirred for 15 minutes. The mixture was extracted with CH₂Cl₂, washed with brine, dried over MgSO₄ and concentrated. Chromatography on silica gel (25:1:0.05 CH₂Cl₂/MeOH/NH₃—H₂O as eluant) provided 383 (145 mg, 87% yield) as a white foam. Data for 383: MS (ESI) m/z 1112.7 (M+H)⁺, 557.1 (100%); ¹HNMR (300 MHz, CDCl₃, partial): δ 7.70 (d, J=9 Hz, 2H), 7.61 (s, 1H), 7.60 (d, J=9 Hz, 2H), 3.32 (s, 3H), 2.66 (s, 6H), 2.28 (s, 3H), 2.26 (s, 3H), 0.87 (t, J=8 Hz, 3H).

Synthesis of Triazole 384

A mixture of alkyne 174 (120 mg, 0.15 mmol), azide 445 (54 mg, 0.165 mmol) and copper (I) iodide (28.5 mg, 0.15 mmol) in THF (5 mL) was repeatedly degassed and flushed with argon. Hunig's base (0.26 mL) was introduced and the mixture stirred at room temperature for 12 h. The reaction mixture was poured into saturated NH₄Cl (30 mL) and stirred for 15 minutes. The mixture was extracted with CH₂Cl₂, washed with brine, dried over MgSO₄ and concentrated. Chromatography on silica gel (25:1:0.05 CH₂Cl₂/MeOH/NH₃—H₂O as eluant) provided 384 (150 mg, 89% yield) as a white foam. Data for 384: MS (ESI) m/z 1126.7 (M+H)⁺, 564.1 (100%); ¹HNMR (300 MHz, CDCl₃, partial): δ 7.74 (d, J=9 Hz, 2H), 7.60 (d, J=9 Hz, 2H), 7.52 (s, 1H), 3.33 (s, 3H), 2.68 (s, 6H), 2.32 (s, 3H), 2.23 (s, 3H), 0.89 (t, J=8 Hz, 3H).

Example 51 Synthesis of Triazoles 385-389

Scheme 73 depicts the synthesis of triazole 385. 3-Chloro-4-methoxyaniline was converted to carbamate 456 which was subsequently parlayed to azide 459. The cycloaddition of 459 with alkyne 173 afforded triazole 385. The same chemistry depicted in Scheme 73 was used to synthesize triazoles 386-389 from the appropriate anilines.

Synthesis of Azide 459

Sodium bicarbonate (2.69 g, 25.4 mmol) was dissolved in water (22 mL) and (45 mL) acetone. To this solution p-anisidine (2.0 g, 12.7 mmol) was added. The mixture was cooled to 0° C., and benzyl chloroformate (1.81 mL, 12.70 mmol) was added. The mixture was stirred 5 min at 0° C., the cold bath removed, and then stirring was continued at room temperature overnight (−16 hours). The mixture was evaporated, and partitioned with a 1:1 mixture of ethyl acetate and water. The organic layer was washed with water, and then brine. The organic layer was dried with Na₂SO₄, and evaporated to yield carbamate 456 (3.20 g, 86% yield) of suitable purity for use in subsequent reactions. Data for 456: ¹HNMR (300 MHz, CDCl₃): δ 7.50 (s, 1H), 7.30 (m, 5H), 7.10 (d, J=5 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 5.15 (s, 2H), 3.84 (s, 3H).

Carbamate 456 (1.0 g, 3.43 mmol) was dissolved in 50 mL tetrahydrofuran, and the solution cooled to −78° C. n-Butyllithium (2.5 M in hexane, 2.1 mL, 3.43 mmol) was added slowly, and the mixture allowed to stir for 45 min at −78° C. R-Glycidyl butyrate (0.5 mL, 3.5 mmol) was added, and the mixture was stirred for 1 h at −78° C. The bath was removed and the reaction allowed to stir overnight at room temperature. The reaction was quenched with 10 mL saturated ammonium chloride solution, and partitioned with ethyl acetate and water. The aqueous layer was extracted thrice with ethyl acetate, and the combined organic layer was washed with brine, dried (Na₂SO₄), and evaporated to yield alcohol 457 (0.5 g, 63% yield) of suitable purity for use in subsequent reactions. Data for 457: ¹HNMR (300 MHz, CDCl₃): δ 7.49 (s, 1H), 7.35 (m, 1H), 6.84 (d, J=5 Hz, 1H), 4.71 (m, 1H), 3.95 (m, 2H).

Alcohol 457 (0.5 g, 1.94 mmol) was dissolved in 5 mL methylene chloride, and the mixture cooled to 0° C. Triethylamine (0.54 mL, 3.88 mmol) was added, followed by methanesulfonyl chloride (0.2 mL, 2.72 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hr. Methylene chloride (10 mL) was added, and the mixture washed twice with 1N HCl, then twice with 10% aqueous sodium carbonate, and then brine. The organic phase was dried (Na₂SO₄), and evaporated to yield mesylate 458 (0.60 g, 92% yield).

A solution of mesylate 458 (0.60 g, 1.79 mmol) in dimethylformamide (5 mL) was treated with sodium azide (0.46 g, 7.15 mmol) and the mixture heated to 80° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 459 (0.45 g, 90% yield) as a yellow solid of suitable purity for use in subsequent reactions. Data for 459: ¹HNMR (300 MHz, CDCl₃): δ 7.50 (s, 1H), 7.35 (dd, J=2, 5 Hz, 1H), 6.87 (d, J=9 Hz, 1H), 4.75 (m, 1H), 4.0 (t, J=9 Hz, 1H), 3.75 (dd, J=9, 13 Hz, 1H), 3.52 (dd, J=5, 13 Hz, 1H).

Synthesis of Triazole 385

A solution of but-3-ynyl-methyl-amino azithromycin 173 (100 mg, 0.127 mmol) in tetrahydrofuran (5 mL) was treated with azide 459 (53.0 mg, 0.19 mmol), N,N-diisopropylethylamine (0.026 mL, 0.15 mmol) and copper (I) iodide (0.018 g, 0.095 mmol), and the mixture was stirred under argon at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried and evaporated. The residue was purified by preparative thin layer chromatography (using 80% CH₂Cl₂, 20% MeOH, 1% NH₄OH as eluant) to provide triazole 385 (64 mg, 50% yield) as a white solid. Data for 385: ¹HNMR (300 MHz, CDCl₃, partial): δ 7.60 (s, 1H), 7.40 (s, 1H), 7.10 (s, 1H), 6.80 (d, J=3 Hz, 1H), 4.95 (m, 1H), 4.60 (m, 1H), 4.40 (m, 1H), 4.20 (m, 1H), 4.0 (m, 1H), 3.50 (m, 1H), 3.20 (s, 2H).

Synthesis of Triazoles 386-389

The azides required for the synthesis of triazoles 386-389 were synthesized from the appropriate amines using the chemistry reported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673). The azides were treated with alkyne 173, using the conditions reported above for the synthesis of triazole 385, to afford the targets 386-389.

Data for 386: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 5.0 (s, 1H), 4.80 (m, 1H), 4.60 (m, 2H), 4.47 (m, 2H), 3.98-4.20 (m, 5H), 3.60 (m, 2H), 3.25 (d, J=6 Hz, 3H), 2.20 (m, 3H).

Data for 387: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.46 (s, 1H), 7.37 (d, J=2 Hz, 2H), 7.20 (m, 2H), 5.10 (s, 1H), 5.00 (m, 2H), 4.70 (m, 2H), 4.45 (d, J=3 Hz, 1H), 4.20 (s, 1H), 4.15 (m, 3H).

Data for 388: ¹H-NMR (300 MHz, CDCl₃, partial): δ 9.0 (s, 1H), 7.50 (m, 4H), 5.0 (m, 2H), 4.70 (m, 3H), 4.30 (d, J=2 Hz, 1H), 4.20 (s, 1H), 4.10 (m, 1H), 4.0 (m, 1H), 3.98 (m, 1H), 3.60 (m, 2H), 3.20 (m, 3H), 2.98 (t, J=7 Hz, 1H).

Data for 389: ¹H-NMR (300 MHz, CDCl₃, partial): δ 9.20 (s, 1H), 7.50 (s, 1H), 7.30 (m, 2H), 6.80 (m, 1H), 5.10 (d, J=5 Hz, 1H), 4.98 (m, 1H), 4.80 (d, J=3 Hz, 1H), 4.60 (m, 2H), 4.30 (d, J=2 Hz, 1H), 4.20 (s, 1H), 4.0 (m, 2H), 3.80 (s, 3H), 3.60 (m, 2H), 3.27 (s, 3H), 3.11 (app t, J=7 Hz, 1H).

Example 52 Synthesis of Triazole 390

Scheme 74 depicts the synthesis of triazole 390. The cycloaddition of dibromo hydroxyformimine and allyl alcohol provided bromo isoxazoline 460 which was then converted into alcohol 461. The alcohol of 461 was transformed to the azide 462 which underwent cycloaddition to alkyne 173 to afford triazole 390.

Synthesis of Isoxazoline 460

A mixture of dibromo hydroxyformimine (1 g, 4.93 mmol), allyl alcohol (1.68 mL, 24.7 mmol), NaHCO₃ (1.58 g, 18.7 mmol) in 1.5 mL water and 18 mL ethyl acetate was stirred over night at room temperature. The mixture was then poured into 20 mL of water and extracted with ethyl acetate (2×20 mL). The combined organic extract was washed with brine (10 mL), dried (Na₂SO₄) and evaporated, yielding 460 (828 mg, 93%). Data for 460: ¹HNMR (300 MHz, CDCl₃): δ 4.80-4.65 (m, 1H), 3.85-3.74 (m, 1H), 3.61-3.52 (m, 1H), 3.22-3.05 (m, 2H), 1.95-1.75 (br s, 1H).

Synthesis of Alcohol 461

To a solution of 1-butanol (5.1 mL, 55.6 mmol) in 25 mL DMSO was added a 2.5 M n-BuLi solution in hexanes (3.9 mL, 9.72 mmol). The mixture was stirred at room temperature for 20 min, then a solution of 460 (500 mg, 2.78 mmol) in 2 mL DMSO was added. The mixture was stirred at room temperature for 3 h, poured into 50 mL water/ice and extracted with ethyl acetate (3×40 mL). The combined organic extract was washed with water (4×20 mL), brine (20 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: hexanes-ethyl acetate 2:1) yielding 461 (165 mg, 34%). Data for 461: ¹HNMR (300 MHz, CDCl₃): δ 4.69-4.60 (m, 1H), 4.09-4.00 (m, 2H), 3.78-3.69 (m, 1H), 3.59-3.51 (m, 1H), 2.99-2.78 (m, 2H), 1.68-1.55 (m, 2H), 1.40-1.25 (m, 2H), 0.90-0.82 (m, 3H).

Synthesis of Azide 462

To a solution of 461 (165 mg, 0.95 mmol) in 3 mL dichloromethane was added Et₃N (0.24 mL, 1.72 mmol) followed by MsCl (0.089 mL, 1.14 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, poured into 10 mL water/ice and extracted with dichloromethane (2×10 mL). The combined organic extract was washed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was dissolved in 3 mL DMF, NaN₃ (124 mg, 1.91 mmol) was added, and the mixture was stirred at 80° C. for 2 h. The mixture was poured into 10 mL water/ice and extracted with ethyl acetate (2×10 mL). The combined organic extract was washed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: hexanes-ethyl acetate 3:1) yielding 462 (155 mg, 82%). Data for 462: ¹HNMR (300 MHz, CDCl₃): δ 4.98-4.85 (m, 1H), 4.31-4.25 (m, 2H), 3.72-3.51 (m, 2H), 3.25-3.15 (m, 1H), 3.05-2.91 (m, 1H), 1.92-1.81 (m, 2H), 1.62-1.50 (m, 2H), 1.15-1.05 (m, 3H).

Synthesis of Triazole 390

To a solution of alkyne 173 (150 mg, 0.191 mmol) in 6 mL acetonitrile was added 462 (37.8 mg, 0.191 mmol), 2,6-lutidine (0.025 mL, 0.209 mmol) and CuI (18.2 mg, 0.095 mmol). The mixture was stirred over night at room temperature, then poured into 10 mL 5% aqueous NH₃/ice and extracted with CH₂Cl₂/isopropanol 95:5 (3×20 mL). The combined organic extract was washed with brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-MeOH 5:1) yielding 390 (131 mg, 70%). Data for 390: MS (ESI) m/z 985 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.25-8.05 (br s, 1H) 7.66 (s, 1H), 5.12-4.90 (m, 3H).

Example 53 Synthesis of Triazoles 391-393

Scheme 75 depicts the synthesis of triazole 391. The oxime of 2,4-dichlorobenzaldehyde was converted to hydroxyiminoyl chloride 464 prior to cycloaddition to alcohol 465. Conversion of alcohol 465 to azide 466 and final cycloaddition to alkyne 173 afforded triazole 391. Triazoles 392 and 393 were synthesized in the same manner as compound 391.

Synthesis of oxime 463

To a suspension of 2,4-dichlorobenzenecarboxaldehyde (7.73 g, 44.2 mmol) in 100 mL 95% aqueous EtOH was added HCl-H₂NOH (3.69 g, 53.0 mmol) followed by a solution of NaOH (2.3 g, 57.4 mmol) in 4 mL of water at 0° C. The suspension was stirred at room temperature overnight, poured into 300 mL ice/water and extracted with ethyl acetate (2×100 mL). The combined organic extract was washed with water (2×80 mL), brine (80 mL), dried (Na₂SO₄) and evaporated yielding 463 (8.2 g, 97%). Data for 463: ¹HNMR (300 MHz, CDCl₃): δ 8.52 (s, 1H), 7.80-8.75 (m, 1H), 7.43-7.40 (m, 1H), 7.29-7.20 (m, 1H).

Synthesis of hydroxyiminoyl chloride 464

To a solution of 463 (7.0 g, 36.8 mmol) in 30 mL DMF was added in portions N-chlorosuccinimide (5.4 g, 40.5 mmol) at 20-30° C. The mixture was stirred at room temperature for 1 h, then poured into 200 mL ice/water and extracted with ethyl acetate (2×100 mL). The combined organic extract was washed with water (3×80 mL), brine (80 mL), dried (Na₂SO₄) and evaporated yielding 464 (7.1 g, 86%). Data for 464: ¹HNMR (300 MHz, CDCl₃): δ 8.64 (s, 1H), 7.38-7.15 (m, 3H).

Synthesis of Alcohol 465

To a solution of allyl alcohol (1.33 mL, 19.6 mmol) in 58 mL CHCl₃ was added a 1M diethylzinc solution in hexanes (23.2 mL, 23.2 mmol) at −5 to 0° C. After stirring for 10 min, (+)-diisopropyl tartrate (0.75 mL, 3.56 mmol) was added and the solution was stirred for 1 h at 0° C. The milky solution was cooled to −20° C. and 14 mL CHCl₃ and dioxane (1.97 mL, 23.2 mmol) was added. Then 464 (4.00 g, 17.8 mmol) was added in portions at −20 to −15° C. The solution was stirred for 4 h at −10° C., then poured into 200 mL 1M citric acid/ice and extracted with CHCl₃ (3×100 mL). The combined organic extract was washed with brine (80 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-hexanes 2:3), yielding crude 465, which was recrystallized from 1-chlorobutane, yielding pure 465 (2.6 g, 60%). Data for 465: ¹HNMR (300 MHz, CDCl₃,): δ 7.76 (d, J=5 Hz, 1H), 7.61 (s, 1H), 7.49-7.42 (m, 1H), 5.10-5.01 (m, 1H), 4.07 (dd, J=3, 12 Hz, 1H), 4.03 (dd, J=3, 12 Hz, 1H), 3.73-3.52 (m, 2H), 2.18 (br s, 1H).

Synthesis of Azide 466

To a solution of 465 (1.0 g, 4.1 mmol) in 20 mL dichloromethane was added Et₃N (1.0 mL, 7.3 mmol) followed by MsCl (0.37 mL, 4.9 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, poured into 50 mL water/ice and extracted with dichloromethane (2×40 mL). The combined organic extract was washed with water (2×20 mL), brine (20 mL), dried (Na₂SO₄) and evaporated. The residue was dissolved in 17 mL DMF, NaN₃ (0.53 g, 8.1 mmol) was added, and the mixture was stirred at 80° C. for 2 h. The mixture was poured into 50 mL water/ice and extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with water (3×20 mL), brine (20 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: hexanes-ethyl acetate 2:3) yielding 466 (1.1 g, 98%).

Data for 466: ¹HNMR (300 MHz, CDCl₃,): δ 7.65 (d, J=8 Hz, 1H), 7.61 (d, J=1 Hz, 1H), 7.23-7.17 (m, 1H), 4.90-4.82 (m, 1H), 3.61-3.21 (m, 4H).

Synthesis of Triazole 391

To a solution of alkyne 173 (150 mg, 0.191 mmol) in 6 mL acetonitrile was added azide 466 (52 mg, 0.191 mmol), 2,6-lutidine (0.025 mL, 0.209 mmol) and CuI (18.2 mg, 0.095 mmol). The mixture was stirred overnight at room temperature, poured into 10 mL 5% aqueous NH₃/ice and extracted with CH₂Cl₂/isopropanol 95:5 (3×20 mL). The combined organic extract was washed with brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-MeOH 5:1) yielding 391 (157 mg, 78%). Data for 391: MS (ESI) m/z 1057 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.30-8.10 (br s, 1H), 7.52 (s, 1H), 7.39-7.20 (m, 3H), 5.15-5-02 (m, 1H).

Synthesis of Triazole 392

To a suspension of 4-chloro-3-fluorobenzaldehyde (5.00 g, 31.5 mmol) in 90 mL 95% aqueous EtOH was added HCl.H₂NOH (2.63 g, 37.8 mmol) followed by a solution of NaOH (1.90 g, 47.3 mmol) in 3 mL of water at 0° C. The suspension was stirred at room temperature for 3 h, then poured into 200 mL ice/water and extracted with ethyl acetate (2×100 mL). The combined organic extract was washed with water (2×80 mL), brine (80 mL), dried (Na₂SO₄) and evaporated. The residue was dissolved in 25 mL DMF and N-chlorosuccinimide (4.23 g, 34.7 mmol) was added in portions at 30-40° C. The mixture was stirred at room temperature for 1 h, then poured into 200 mL ice/water and extracted with ethyl acetate (2×100 mL). The combined organic extract was washed with water (3×80 mL), brine (80 mL), dried (Na₂SO₄) and evaporated yielding the hydroxyiminoyl chloride (3.71 g., 62%). Data: ¹HNMR (300 MHz, CDCl₃,): δ 8.15 (s, 1H), 7.60-7.51 (m, 2H), 7.41-7.32 (m, 1H).

To a solution of allyl alcohol (1.16 mL, 17.0 mmol) in 50 mL CHCl₃ at −5 to 0° C. was added a 1 M diethylzinc solution in hexanes (20.1 mL, 20.1 mmol). After stirring for 10 min, (+)-diisopropyl tartrate (0.65 mL, 3.09 mmol) was added and the solution was stirred for 1 h at 0° C. The milky solution was cooled to −20° C. and 12 mL CHCl₃ and dioxane (1.70 mL, 20.1 mmol) was added. Then the above hydroxyiminoyl chloride (3.21 g, 15.4 mmol) was added in portions at −20 to −15° C. The solution was stirred for 3 h at −15° C., then poured into 200 mL 1 M citric acid/ice and extracted with CHCl₃ (3×100 mL). The combined organic extract was washed with brine (80 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-hexanes 1:2 and 1:2), yielding crude material which was recrystallized twice from 1-chlorobutane, yielding the expected isoxazoline alcohol (1.5 g, 42%). Data: ¹HNMR (300 MHz, CDCl₃,): δ 7.48-7.21 (m, 3H), 4.82-4-74 (m, 1H), 3.82-3.76 (m, 1H), 3.58-3.53 (m, 1H), 3.27-3.09 (m, 2H).

To a solution of the above alcohol (1.0 g, 4.4 mmol) in 20 mL dichloromethane was added Et₃N (1.1 mL, 7.8 mmol) followed by MsCl (0.41 mL, 5.2 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, then poured into 50 mL water/ice and extracted with dichloromethane (2×40 mL). The combined organic extract was washed with water (2×20 mL), brine (20 mL), dried (Na₂SO₄) and evaporated. The residue was dissolved in 15 mL DMF, NaN₃ (0.57 g, 8.7 mmol) was added and the mixture was stirred at 80° C. for 2 h. The mixture was poured into 50 mL water/ice and extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with water (3×20 mL), brine (20 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: hexanes-ethyl acetate 2:3) yielding the expected azide (1.1 g, 95%). Data: ¹HNMR (300 MHz, CDCl₃,): δ 7.43-7.29 (m, 3H), 4.93-4.84 (m, 1H), 3.54-3.27 (m, 3H), 3.18-3.30 (m, 1H).

To a solution of alkyne 173 (150 mg, 0.191 mmol) in 6 mL acetonitrile was added the above azide (49.5 mg, 0.191 mmol), 2,6-lutidine (0.0245 mL, 0.209 mmol) and CuI (18.2 mg, 0.095 mmol). The mixture was stirred overnight at room temperature, poured into 10 mL 5% aqueous NH₃/ice and extracted with CH₂Cl₂/isopropanol 95:5 (3×20 mL). The combined organic extract was washed with brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-MeOH 5:1) yielding 392 (138 mg, 70%). Data for 392: MS (ESI) m/z 1042 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.45-8.32 (br s, 1H), 7.28-7.19 (m, 2H), 7.13-7.10 (m, 1H), 5.05-4.82 (m, 2H).

Synthesis of Triazole 393

To a solution of alkyne 173 (150 mg, 0.191 mmol) in 6 mL acetonitrile was added azide 342 (45.4 mg, 0.191 mmol), 2,6-lutidine (0.025 mL, 0.209 mmol) and CuI (18.2 mg, 0.095 mmol). The mixture was stirred overnight at room temperature, then poured into 10 mL 5% aqueous NH₃/ice and extracted with CH₂Cl₂/isopropanol 95:5 (3×20 mL). The combined organic extract was washed with brine (10 mL), dried (Na₂SO₄) and evaporated. The residue was purified by flash-chromatography (eluant: ethyl acetate-MeOH 5:1) yielding 393 (118 mg, 60%). Data for 393: MS (ESI) m/z 1025 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.00 (br s, 1H), 7.52 (m, 3H), 5.11-4.95 (m, 1H), 4.95-4.82 (m, 2H).

Example 54 Synthesis of Triazoles 394-403

Scheme 76 depicts the synthesis of azides 469, 482-487, 489, 491, and 495 required for the synthesis of triazoles 394-403. The azides were then treated with alkyne 173 to afford the final targets.

Synthesis of hydroxyiminoyl chloride 467

To a solution of 3-formyl-6-fluoropyridine (1.77 g, 9.36 mmol) in EtOH (10 mL) at 0° C. was added water (5 mL), then hydroxylamine (1.00 g, 14.0 mmol), followed by the addition of NaOH (2.20 mL, 50% w/w). The mixture was stirred at 0° C. for 15 min. The EtOH was evaporated, then EtOAc (50 mL) was added. HCl (1 M) was used to the adjust pH to 6. The aqueous phase was extracted with EtOAc (30 mL×2), and the organic extracts were dried by Na₂SO₄. The concentrated residue (1.50 g) was used in the next step without further purification.

To a solution of the crude intermediate above (1.50 g, in DMF (20 mL) at room temperature was added N-chlorosuccinimide (1.80 g, 13.1 mmol) in two portions. The mixture was stirred at 45-50° C. for 1 h, then brine (50 mL) and saturated aqueous Na₂CO₃ (3 mL) was added. The mixture was extracted with EtOAc/Hexane (200 mL, 1/1). The organic layer was washed by brine (200 mL), dried by MgSO₄, to give hydroximinoyl chloride 467 (1.45 g, 60% yield). Data for 467: ¹HNMR (300 MHz, CDCl₃): δ 8.72 (d, J=3 Hz, 1H), 8.45 (s, 1H), 8.30-8.20 (m, 1H), 7.00 (dd, J=9, 3 Hz, 1H).

Synthesis of Hydroxyiminoyl Chlorides 470-475

These hydroxyiminoyl chlorides were synthesized from the appropriate aryl aldehyde using the above procedure for the synthesis of 467.

Data for 470: ¹HNMR (300 MHz, CDCl₃): δ 9.27 (s, 1H), 8.86 (d, J=3 Hz, 1H), 7.90-7.70 (m, 1H), 7.54 (d, J=8 Hz, 1H).

Data for 471: ¹HNMR (300 MHz, CDCl₃): δ 8.16 (s, 1H), 7.94 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H).

Data for 472: ¹HNMR (300 MHz, CDCl₃): δ 8.53 (s, 1H), 8.02 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz, 1H).

Data for 475: ¹HNMR (300 MHz, CDCl₃): δ 8.08 (s, 1H), 7.58-7.22 (m, 1H).

Synthesis of Alcohol 468

To a solution of allyl alcohol (661 μL, 9.62 mmol) in CHCl₃ (30 mL) at 0° C. was added diethylzinc (12.03 mL, 12.03 mmol). After the mixture was stirred at 0° C. for 15 min, (+)-diisopropyl tartrate (855 μL, 4.01 mmol) in CHCl₃ (5.0 mL) was added. The mixture was stirred at 0° C. for 1 h, then hydroximinoyl chloride 467 (1.40 g, 8.02 mmol) in CHCl₃ (10.0 mL) was added dropwise over 10 min. The mixture was stirred at 0° C. for 2 h, then sat. aqueous NH₄Cl (20 mL) and citric acid (6 mL, 1 M) was added. The mixture was extracted with CH₂Cl₂ (50 mL×4), and the organic extracts were dried by Na₂SO₄. The residue was purified by flash-chromatography (eluant: 2.5/100 MeOH/CH₂Cl₂), to provide 468 (1.40 g, 89% yield; >95% ee).

Data for 468: ¹HNMR (300 MHz, CDCl₃): δ 8.39 (d, J=3 Hz, 1H), 8.25-8.15 (m, 1H), 7.00 (dd, J=9, 3 Hz, 1H), 4.98-4.88 (m, 1H), 3.94 (dd, J=12, 3 Hz, 1H), 3.72 (dd, J=12, 4 Hz, 1H), 3.69-3.25 (m, 2H).

Synthesis of Alcohols 476-481

These alcohols were synthesized from the appropriate hydroxyiminoyl chlorides using the above procedure for the synthesis of 468.

Data for 476: ¹HNMR (300 MHz, CDCl₃): δ 8.54 (d, J=3 Hz, 1H), 7.92 (dd, J=11, 3 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 4.99-4.90 (m, 1H), 3.94 (dd, J=12, 3 Hz, 1H), 3.71 (dd, J=12, 4 Hz, 1H), 3.47-3.93 (m, 2H).

Data for 477: ¹HNMR (300 MHz, CDCl₃): δ 7.77 (d, J=8 Hz, 2H), 7.65 (d, J=8 Hz, 2H), 4.93 (dddd, J=13, 8, 4, 3 Hz, 1H), 3.93 (dd, J=13, 3 Hz, 1H), 3.70 (dd, J=13, 4 Hz, 1H), 3.40 (dd, J=17, 11 Hz, 1H), 3.32 (dd, J=17, 8 Hz, 1H).

Data for 478: ¹HNMR (300 MHz, CDCl₃): δ 7.87 (d, J=8 Hz, 1H), 7.84 (d, J=8 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 4.93 (dddd, J=13, 8, 3, 3 Hz, 1H), 3.92 (dd, J=13, 3 Hz, 1H), 3.70 (dd, J=13, 4 Hz, 1H), 3.43 (dd, J=11, 7 Hz, 1H), 3.33 (dd, J=11, 8 Hz, 1H).

Data for 479: ¹HNMR (300 MHz, CDCl₃): δ 7.76 (d, J=7 Hz, 2H), 7.31 (d, J=7 Hz, 2H), 4.96 (dddd, J=13, 8, 4, 3 Hz, 1H), 3.96 (dd, J=12, 3 Hz, 1H), 3.75 (dd, J=12, 5 Hz), 3.44 (dd, J=17, 10 Hz, 1H), 3.34 (dd, J=17, 8 Hz, 1H).

Data for 480: ¹HNMR (300 MHz, CDCl₃): δ 7.58 (d, J=8 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J=8 Hz, 1H), 7.31-7.24 (m, 1H), 4.92 (dddd, J=12, 8, 4, 3 Hz, 1H), 3.94 (dd, J=5, 3 Hz, 1H), 3.90 (dd, J=5, 3 Hz, 1H), 3.72 (dd, J=8, 4 Hz, 1H), 3.68 (dd, J=8, 4 Hz, 1H).

Data for 481: ¹HNMR (300 MHz, CDCl₃): δ 7.27 (s, 1H), 7.20 (s, 1H), 4.83 (dddd, J=12, 8, 3, 3 Hz, 1H), 3.87 (dd, J=12, 3 Hz, 1H), 3.67 (dd, J=12, 4 Hz, 1H), 3.37-3.17 (m, 2H).

Synthesis of Azide 469

To a solution of alcohol 468 (700 mg, 3.57 mmol) in CH₂Cl₂ (20 mL) at 0° C. was added Et₃N, followed by the addition of MsCl (416 μL, 5.35 mmol). The mixture was stirred at 0° C. for 30 min, then EtOAc (100 mL) was added, and the mixture was washed with brine (100 mL×2), dried with MgSO₄, and evaporated to afford the crude mesylate (800 mg).

A mixture of the above mesylate (800 mg, 3.57 mmol) and NaN₃ in DMF (15 mL) was stirred at 80° C. for 3 h, then the mixture was poured into water (50 mL), extracted with Et₂O (30 mL×3), dried with Na₂SO₄, and evaporated to afford azide 469 (540 mg, 68% yield). Data for 469: ¹HNMR (300 MHz, CDCl₃): δ 8.39 (s, 1H), 8.30-8.20 (m, 1H), 7.03 (dd, J=8, 3 Hz, 1H), 4.40-4.30 (m, 1H), 3.60 (dd, J=10, 5 Hz, 1H), 3.55-3.35 (m, 2H), 3.25 (dd, J=16, 7 Hz, 1H).

Synthesis of Azides 482-487

These azides were synthesized from the appropriate alcohols using the above procedure for the synthesis of 469.

Data for 482: ¹HNMR (300 MHz, CDCl₃): δ 8.46 (d, J=3 Hz, 1H), 7.88 (dd, J=9, 2 Hz, 1H), 7.49 (dd, J=9, 2 Hz, 1H), 5.00-4.80 (m, 1H), 3.53 (dd, J=10, 4 Hz, 1H), 3.53-3.30 (m, 2H), 3.16 (dd, J=17, 7 Hz, 1H).

Data for 483: ¹HNMR (300 MHz, CDCl₃): δ 7.79 (d, J=8 Hz, 2H), 7.68 (d, J=8 Hz, 2H), 5.13-5.02 (m, 1H), 4.43 (dd, J=11, 4 Hz, 1H), 4.37 (dd, J=11, 5 Hz, 1H), 3.53 (dd, J=17, 11 Hz, 1H), 3.33 (dd, J=9, 7 Hz, 1H).

Data for 484: ¹HNMR (300 MHz, CDCl₃): δ 7.87 (dd, J=9, 9 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.56 (dd, J=8, 8 Hz, 1H), 5.13-5.02 (m, 1H), 4.46-4.30 (m, 2H), 3.53 (dd, J=17, 11 Hz, 1H), 3.36 (dd, J=9, 7 Hz, 1H).

Data for 485: ¹HNMR (300 MHz, CDCl₃): δ 7.65 (d, J=9 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 4.93-4.85 (m, 1H), 3.50 (dd, J=13, 5 Hz, 1H), 3.43-3.30 (m, 2H), 3.15 (dd, J=13, 7 Hz, 1H).

Data for 486: ¹HNMR (300 MHz, CDCl₃): δ 7.67-750 (m, 4H), 4.94-4.84 (m, 1H), 3.50 (dd, J=13, 5 Hz, 1H), 3.45-3.25 (m, 2H), 3.20 (dd, J=13, 7 Hz, 1H).

Data for 487: ¹HNMR (300 MHz, CDCl₃): δ 7.67-750 (m, 4H), 4.94-4.84 (m, 1H), 3.50 (dd, J=13, 5 Hz, 1H), 3.45-3.25 (m, 2H), 3.20 (dd, J=13, 7 Hz, 1H).

Synthesis of Alcohol 488

A mixture of alcohol 348 (310 mg, 1.21 mmol), 3-(tributyl)stannylpyridine (446 mg, 1.21 mmol), Pd(dppf)₂Cl₂ (59 mg, 0.072 mmol), copper (I) chloride (12 mg), lithium chloride (305 mg, 7.20 mmol) in DMSO (3.0 mL) was degassed by argon and then was stirred at 60° C. for 16 h. The reaction was quenched by the addition of H₂O (50 mL), NH₄OH (0.2 mL), EtOAc (150 mL) and CH₂Cl₂ (20 mL). The mixture was passed through celite. The organic layer was washed with water (50 mL×3), dried with Na₂SO₄, and the residue was purified by flash-chromatography (eluant: MeOH/CH₂Cl₂, 2/100), to give 488 (265 mg). Data for 488: ¹HNMR (300 MHz, CDCl₃): δ 8.88 (s, 1H), 8.63 (d, J=4 Hz, 1H), 7.92 (d, J=8 Hz, 1H), 7.89 (d, J=8 Hz, 2H), 7.64 (d, J=8 Hz, 1H), 7.41 (dd, J=8, 5 Hz, 1H), 4.92 (dddd, J=12, 8, 3, 3 Hz, 1H), 3.92 (dd, J=12, 3 Hz, 1H), 3.72 (dd, J=12, 5 Hz, 1H), 3.44 (dd, J=17, 11 Hz, 1H), 3.33 (dd, J=17, 8 Hz, 1H).

Synthesis of Azide 489

The azide was synthesized using the same procedure as described above for the synthesis of azide 469. Data for 489: ¹HNMR (300 MHz, CDCl₃): δ 8.85 (s, 1H), 8.60 (m, 1H), 7.85 (d, J=8 Hz, 1H), 7.73 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 7.36 (s, 1H), 4.96-4.84 (m, 1H), 3.54 (dd, J=13, 5 Hz, 1H), 3.45-3.35 (m, 2H), 3.20 (dd, J=13, 7 Hz, 1H).

Synthesis of Alcohol 490

This compound was synthesized from alcohol 476 using the procedure described above for the synthesis of 488. Data for 490: ¹HNMR (300 MHz, CDCl₃): δ 9.17 (s, 1H), 8.86 (d, J=2 Hz, 1H), 8.62 (s, 1H), 8.30 (d, J=8 Hz, 1H), 8.08 (dd, J=8, 2 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.37 (dd, J=8, 5 Hz, 1H), 4.93-4.84 (m 1H), 3.88 (d, J=10 Hz, 1H), 3.66 (d, J=10 Hz, 1H), 3.44-3.20 (m, 2H).

Synthesis of Azide 491

This azide was synthesized from alcohol 490 using the same procedure described above for the synthesis of azide 469. Data for 491: ¹HNMR (300 MHz, CDCl₃): δ 8.82 (s, 1H), 8.30-8.20 (m, 2H), 8.28-8.18 (m, 2H), 7.76 (d, J=9 Hz, 1H), 7.40 (s, 1H), 4.96-4.86 (m, 1H), 3.59-3.20 (m, 4H), 3.20 (dd, J=13, 7 Hz, 1H).

Synthesis of Silylether 493

To a solution of alcohol 460 (360 mg, 2.00 mmol) in DMF (8.0 mL) at 0° C. was added t-butyldimethylsilyl chloride (461 mg, 3.00 mmol), followed by the addition of imidazole (275 mg, 4.0 mmol). The mixture was stirred at 0° C. for 1 h and room temperature for 16 h. Water (50 mL) was added, and the mixture was extracted with 30% EtOAc in hexane (50 mL×3). The organic phase was washed with water (50 mL×2), dried by Na₂SO₄, and evaporated. The residue was purified by flash-chromatography (eluant: EtOAc/hexane, 5/95), to afford 493 (580 mg, 98% yield). Data for 493: ¹HNMR (300 MHz, CDCl₃, ppm): δ 4.70-4.61 (m, 1H), 3.69 (dd, J=11, 4 Hz, 1H), 3.62 (dd, J=11, 4 Hz, 1H), 0.81 (s, 9H), 0.01 (s, 6H).

Synthesis of Azide 495

Alcohol 348 (1.00 g, 3.90 mmol) and PdCl₂(dppf)₂ (546 mg, 0.762 mmol) were dissolved in dioxane (11 mL) and hexamethylditin (1.42 g, 4.30 mmol) was added. The mixture was stirred at 85° C. for 16 h, then sat. aqueous NaHCO₃ (20 mL) was added, followed by EtOAc (20 mL). The aqueous phase was extracted with EtOAc (40 mL×3), and the organic phase was dried by Na₂SO₄. The residue was purified by flash-chromatography (eluant: EtOAc/hexane, 35/65) to afford stannane 492 (740 mg, 56% yield). Data for 492: ¹HNMR (300 MHz, CDCl₃): δ 7.13 (d, J=6 Hz, 2H), 7.05 (d, J=6 Hz, 2H), 4.70-4.60 (m, 1H), 3.70-3.61 (m, 3H), 3.51-3.41 (m, 1H), 3.17 (dd, J=17, 11 Hz, 1H), 3.05 (dd, J=17, 8 Hz, 1H), 1.73 (dd, J=8, 6 Hz, 1H), 0.09 (s, 9H).

To a suspension of stannane 492 (340 mg, 1.00 mmol), bromide 493 (353 mg, 1.20 mmol) and lithium chloride (254 mg, 6.00 mmol) in DMSO (2.5 mL) was added PdCl₂(dppf)₂ (49 mg, 0.06 mmol). The mixture was stirred at 70° C. for 16 h, then water (50 mL) was added. The mixture was extracted with EtOAc (40 mL×3), and the extracts were dried by Na₂SO₄. The residue was purified by flash-chromatography (eluant: EtOAc/hexane, 35/65) to afford alcohol 494 (21 mg, 63% yield). Data for 494: ¹HNMR (300 MHz, CDCl₃): δ 7.56 (d, J=8 Hz, 2H), 7.22 (d, J=8 Hz, 2H), 4.90-4.81 (m, 1H), 3.87 (dd, J=16, 3 Hz, 3H), 3.68 (dd, J=16, 5 Hz, 1H), 3.38 (dd, J=17, 8 Hz, 1H), 3.25 (dd, J=17, 8 Hz, 1H), 2.38 (s, 3H).

Azide 495 was synthesized from alcohol 494 using the same procedure described above for the synthesis of azide 469. Data for 495: ¹HNMR (300 MHz, CDCl₃): δ 7.50 (d, J=8 Hz, 2H), 7.15 (d, J=8 Hz, 2H), 4.86-4.76 (m, 1H), 3.45-3.30 (m, 3H), 3.13 (dd, J=17, 7 Hz, 1H).

General Procedure for the Synthesis of Triazoles 394-403

To a mixture of alkyne 173 (100 mg, 0.127 mmol) and the appropriate azide (0.140 mmol, 1.1 eq) in acetonitrile (4.0 mL) at room temperature under argon was added 2,6-lutidine (22 μL, 0.191 mmol, 1.1 eq), followed by addition of copper (I) iodide (12 mg, 0.064 mmol). The mixture was stirred at room temperature for 1.5 to 6 h. After the reaction was complete, 1 mL 5% NH₄OH was added. The mixture was stirred at room temperature for 10 min. The reaction solvent (CH₃CN) was removed under vacuum. The aqueous phase was extracted with CH₂Cl₂ (30 mL×3), and the organic phase was dried over Na₂SO₄. The residue was separated by flash-chromatography (eluant: 20/80 to 30/70 MeOH/EtOAc) on silica gel to afford the desired product.

Data for 394: MS (ESI) m/z 1008.4 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.37 (s, 1H), 8.37-8.00 (m, 1H), 7.60 (s, 1H), 7.00 (dd, J=9, 3 Hz, 1H), 4.45 (d, J=6 Hz, 1H), 4.29 (br s, 1H), 2.24 (s, 3H), 1.04 (d, J=9 Hz, 3H).

Data for 395: MS (ESI) m/z 1070.2 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.45 (s, 1H), 7.73 (dd, J=4, 2 Hz, 1H), 7.47 (d, J=4 Hz, 1H), 4.45 (d, J=6 Hz, 1H), 4.29 (br s, 1H), 2.20 (s, 3H), 0.98 (d, J=9 Hz, 3H).

Data for 396: MS (ESI) m/z 1043.7 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.48 (s, 1H), 7.16 (d, J=7 Hz, 2H), 7.14 (d, J=7 Hz, 2H), 4.36 (d, J=7 Hz, 1H), 4.22 (s, 1H), 2.21 (s, 3H), 0.96 (d, J=8 Hz, 3H).

Data for 397: MS (ESI) m/z 1073.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.64 (d, J=8 Hz, 2H), 7.24 (d, J=8 Hz, 2H), 4.40 (d, J=9 Hz, 1H), 4.28 (s, 1H), 2.27 (s, 3H), 1.04 (d, J=9 Hz, 3H).

Data for 398: MS (ESI) m/z 1073.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.53 (s, 1H), 7.43-7.34 (m, 3H), 7.22 (s, 1H), 4.36 (d, J=7 Hz, 1H), 4.21 (s, 1H), 2.20 (s, 3H), 0.96 (d, J=8 Hz, 3H).

Data for 399: MS (ESI) m/z 1057.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.64 (d, J=8 Hz, 2H), 7.58 (d, J=8 Hz, 1H), 7.51 (br s, 1H), 4.55 (t, J=5 Hz, 2H), 4.36 (d, J=10 Hz, 1H), 4.21 (s, 1H), 2.25 (s, 3H), 0.95 (d, J=8 Hz, 3H).

Data for 400: MS (ESI) m/z 1057.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.78 (s, 1H), 7.70 (d, J=8 Hz, 1H), 7.60 (d, J=8 Hz, 1H), 7.53-7.44 (m, 2H), 4.46 (d, J=7 Hz, 1H), 4.21 (s, 1H), 2.20 (s, 3H), 0.96 (d, J=8 Hz, 3H).

Data for 401: MS (ESI) m/z 1003.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.60 (s, 1H), 7.48 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 4.43 (d, J=7 Hz, 1H), 4.22 (s, 1H), 2.27 (s, 3H), 1.04 (d, J=8 Hz, 3H).

Data for 402: MS (ESI) m/z 1066.9 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.79 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.82 (dt, J=8, 2 Hz, 1H), 7.65 (d, J=8 Hz, 2H), 7.56 (d, J=8 Hz, 2H), 7.53 (s, 1H), 7.33 (dd, J=8, 4 Hz, 1H), 4.37 (d, J=7 Hz, 1H), 4.21 (s, 1H), 2.20 (s, 3H), 0.97 (d, J=8 Hz, 3H).

Data for 403: MS (ESI) m/z 1067.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 9.16 (s, 1H), 8.62 (d, J=4 Hz, 1H), 7.82 (dt, J=8, 2 Hz, 1H), 7.96 (dd, J=6, 2 Hz, 1H), 7.74 (d, J=8 Hz, 1H), 7.51 (s, 1H), 7.37 (dd, J=8, 5 Hz, 1H), 4.36 (d, J=7 Hz, 1H), 4.21 (s, 1H), 2.20 (s, 3H), 0.96 (d, J=8 Hz, 3H).

Example 55 Synthesis of Triazoles 404 and 405 Synthesis of Azide 404

This compound (189 mg) was synthesized from alkyne 174 (150 mg, 0.187 mmol) and azide 349 (58 mg, 0.206 mmol) using the same procedure described above for the synthesis of triazole 361. Data for 404: MS (ESI) m/z 542 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.53-7.50 (m, 3H), 7.45-7.42 (m, 2H), 5.17-5.11 (m, 1H), 5.08 (d, J=4 Hz, 1H), 4.69-4.66 (m, 1H), 4.61 (t, J=5 Hz, 2H), 4.45 (d, J=7 Hz, 1H), 3.33 (s, 3H), 3.03 (t, J=9 Hz, 1H), 2.21 (t, J=5 Hz, 4H), 0.89 (m, 6H).

Synthesis of Azide 405

This compound (175 mg) was made from alkyne 174 (150 mg, 0.187 mmol) and azide

503 (49 mg, 0.206 mmol; see Example 58 for the synthesis of 503) using the same procedure described above for the synthesis of triazole 361. Data for 405: MS (ESI) m/z 520.5 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.49 (s, 1H), 7.12-7.05 (m, 2H), 6.91-6.82 (m, 1H), 5.21-5.13 (m, 1H), 5.12 (d, J=5 Hz, 1H), 4.61 (t, J=4 Hz, 2H), 4.44 (d, J=7 Hz, 1H), 4.29 (br d, J=3 Hz, 1H), 4.13-4.03 (m, 1H), 3.69 (d, J=6 Hz, 1H), 3.65 (d, J=7 Hz, 1H), 3.03 (t, J=10 Hz, 1H), 0.91-0.87 (m, 6H).

Example 56 Synthesis of Triazoles 406-409

These triazoles were synthesized using the procedure described above for the synthesis of triazole 228.

Synthesis of Triazole 406

Alkyne 174 (70 mg, 86 μmol), azide 355 (39 mg, 129 μmol), and CuI (2 mg, 8 μmol) afforded triazole 406 as a white solid (94.1 mg, 83 μmol). Data for 406: MS (ESI) m/z 568 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 9.46 (br s, 1H), 7.69-7.53 (m, 8H), 7.44 (s, 1H), 5.20-5.04 (m, 3H), 4.70-4.58 (m, 2H), 4.41 (d, J=6 Hz, 1H), 4.20 (br s, 1H), 4.12-4.00 (m, 1H), 3.61 (d, J=3 Hz, 1H), 3.56 (d, J=7 Hz, 1H), 3.33 (s, 3H), 3.05-2.93 (m, 2H), 2.29 (s, 3H), 2.18 (s, 3H), 2.10 (d, J=9 Hz, 1H), 1.34-1.14 (m, 17H), 0.91-0.84 (m, 6H): ¹³CNMR (75 MHz, CDCl₃): δ 178.9, 156.3, 148.4, 144.4, 141.0, 132.7, 128.9, 127.6, 127.5, 127.4, 122.3, 118.6, 111.6, 102.9, 94.5, 83.3, 79.2, 78.2, 77.7, 74.2, 73.7, 73.0, 70.6, 70.1, 68.8, 65.9, 65.5, 62.4, 53.1, 52.4, 49.5, 45.3, 42.3, 37.4, 36.8, 36.2, 34.7, 29.6, 27.8, 27.6, 26.9, 26.8, 25.4, 22.0, 21.6, 21.3, 21.2, 18.2, 16.2, 14.5, 11.2, 8.8, 7.9.

Synthesis of Triazole 407

Alkyne 174 (70 mg, 86 μmol), azide 349 (36 mg, 129 μmol), and CuI (2 mg, 8 μmol) afforded triazole 407 as a white solid (89 mg, 80 μmol). Data for 407: MS (ESI) m/z 556, 557 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 9.38 (br s, 1H), 7.54-7.41 (m, 5H), 7.44 (s, 1H), 5.20-4.90 (m, 3H), 4.70-4.58 (m, 3H), 4.49 (d, J=6 Hz, 1H), 4.28 (br s, 1H), 4.12-4.00 (m, 1H), 3.61 (d, J=3 Hz, 1H), 3.32 (s, 3H), 3.05-2.93 (m, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 2.15 (d, J=9 Hz, 1H), 1.33-1.27 (m, 6H), 1.27-1.15 (m, 10H), 1.10-1.00 (m, 8H), 0.91-0.84 (m, 6H): ¹³CNMR (75 MHz, CDCl₃): δ 178.8, 156.0, 148.4, 132.0, 128.1, 127.6, 124.8, 122.3, 102.9, 94.5, 83.3, 79.2, 78.2, 77.7, 74.3, 73.7, 73.0, 70.6, 70.1, 68.8, 65.9, 65.5, 62.4, 53.4, 53.1, 52.4, 49.5, 45.3, 42.2, 37.2, 36.8, 36.2, 34.7, 29.6, 27.8, 27.6, 26.9, 26.8, 25.4, 22.0, 21.6, 21.4, 21.3, 18.2, 16.2, 14.6, 11.2, 8.9, 7.4.

Synthesis of Triazole 408

Alkyne 174 (70 mg, 86 μmol), azide 158 (39 mg, 129 μmol), and CuI (2 mg, 8 μmol) afforded triazole 408 as a white solid (93 mg, 85 μmol). Data for 408: MS (ESI) m/z 560 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.70 (br s, 1H), 7.50 (s, 1H), 7.31 (dd, J=14, 2 Hz, 1H), 7.21 (dd, J=8, 2 Hz, 1H), 6.89 (t, J=9 Hz, 3H), 5.14-5.05 (m, 1H), 4.97 (d, J=4 Hz, 1H), 4.65-4.45 (m, 3H), 4.45 (d, J=7 Hz, 1H), 4.28 (dd, J=6, 2 Hz, 1H), 4.13-3.97 (m, 1H), 3.87-3.80 (m, 4H), 3.68-3.61 (m, 3H), 3.32 (s, 3H), 2.28 (s, 3H), 2.18 (d, J=9 Hz, 1H), 2.13 (s, 3H), 1.35-1.15 (m, 18H), 1.10-1.02 (m, 9H), 0.91-0.82 (m, 6H): ¹³CNMR (75 MHz, CDCl₃): δ 178.3, 153.3, 148.3, 133.4, 122.5, 122.3, 118.2, 114.5, 114.2, 103.0, 95.4, 84.0, 79.0, 78.1, 77.6, 77.5, 77.1, 76.6, 73.5, 72.8, 70.7, 70.0, 68.7, 66.7, 65.6, 65.5, 61.8, 53.1, 52.4, 50.4, 50.3, 49.4, 44.9, 42.5, 40.9, 37.4, 36.8, 36.6, 35.0, 29.7, 27.8, 27.3, 26.9, 26.7, 25.4, 21.9, 21.6, 21.4, 18.4, 16.3, 15.5, 11.2, 8.9, 7.4.

Synthesis of Triazole 409

Alkyne 174 (70 mg, 86 μmol), the azide 503 (31 mg, 129 μmol; see Example 58 for the synthesis of 503), and CuI (2 mg, 8 μmol) afforded triazole 409 as a white solid (93 mg, 85 μmol). Data for 409: MS (ESI) m/z 527 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.95 (br s, 1H), 7.47 (s, 1H), 7.12-7.03 (m, 2H), 6.71 (tt, J=9, 2 Hz, 1H), 5.21-5.09 (m, 2H), 4.62 (d, J=6 Hz, 1H), 4.48 (t, J=10 Hz, 1H), 4.45 (d, J=7 Hz, 1H), 4.29 (br s, 1H), 4.15-4.00 (m, 1H), 3.66 (d, J=5 Hz, 1H), 3.62 (d, J=7 Hz, 1H), 3.32 (s, 3H), 3.02 (t, J=11 Hz, 1H), 2.29 (s, 3H), 2.18 (d, J=10 Hz, 1H), 2.13 (s, 3H), 1.77 (d, J=9 Hz, 1H), 1.33-1.26 (m, 6H), 1.27-1.15 (m, 10H), 1.10-0.99 (m, 9H), 0.92-0.84 (m, 6H): ¹³CNMR (75 MHz, CDCl₃, partial): δ 178.7, 155.2, 148.4, 131.6, 122.2, 109.9, 109.8, 109.6, 109.5, 105.7, 02.9, 94.6, 83.4, 79.6, 78.1, 77.9, 76.6, 74.3, 73.9, 73.6, 72.9, 70.6, 70.1, 68.8, 65.8, 65.5, 62.3, 53.1, 52.3, 49.4, 45.2, 42.4, 42.0, 37.0, 36.8, 36.3, 34.8, 29.6, 27.8, 27.5, 27.0, 26.7, 25.4, 21.9, 21.6, 21.3, 21.2, 18.2, 16.2, 11.2, 7.5.

Example 57 Synthesis of Triazoles 410 and 411

These triazoles were synthesized using the chemistry illustrated for triazole 410 shown in Scheme 77. Racemic azide 499 was used to generate triazole 410 as a mixture of diastereomers.

Synthesis of Azide 499

A solution of 3-fluoro-4-methoxybenzaldehyde (2.0 g, 12.97 mmol) and hydroxylamine hydrochloride (1.0 g, 14.27 mmol) in ethanol (40 mL) and water (80 mL) was cooled to 4° C., and 2.3 mL NaOH (50% w/w) was added. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was adjusted to pH 6.0, and partitioned with methylene chloride and water. The aqueous layer was extracted twice with methylene chloride, and the combined organic layer was washed with brine, dried (Na₂SO₄), and evaporated to yield 496 (1.97 g, 90%) as a white solid. Data for 496: ¹HNMR (300 MHz, CDCl₃): δ 7.84 (s, 1H), 7.04 (d, J=3 Hz, 1H), 6.74 (app t, J=8 Hz, 1H).

To a solution of oxime 496 (1.97 g, 11.64 mmol) in dimethylformamide (10 mL) was added N-chlorosuccinimide (1.5 g, 11.64 mmol). The reaction mixture was warmed to 50° C. for 1 h. The reaction was diluted with ethyl acetate (50 mL), and washed with brine. The organic phase was dried (Na₂SO₄), and evaporated to yield 497 (2.37 g, 100% yield). Data for 497: ¹HNMR (300 MHz, CDCl₃): δ 8.02 (s, 1H), 7.60 (m, 1H), 6.94 (t, J=3 Hz, 1H).

To a solution of hydroximinoyl chloride 497 (1.00 g, 4.91 mmol) in methylene chloride (5 mL) was added allyl alcohol (0.3 mL, 4.91 mmol). The mixture was cooled to 0° C., and triethylamine (0.68 mL, 4.91 mmol) was added. The reaction mixture was slowly warmed to room temperature, stirred for 16 h, then quenched with water (20 mL), and extracted twice with methylene chloride. The combined organic layer was washed with brine, dried over (Na₂SO₄), and evaporated to yield 498 (0.76 g, 70% yield). Data for 498: ¹HNMR (300 MHz, CDCl₃): δ 7.40 (m, 1H), 7.30 (m, 1H), 6.80 (m, 1H), 4.80 (m, 1H), 3.60 (s, 3H), 3.20 (m, 2H).

Alcohol 498 (0.7 g, 3.10 mmol) was dissolved in 10 mL methylene chloride, and the mixture cooled to 0° C. Triethylamine (0.86 mL, 6.2 mmol) was added, followed by methanesulfonyl chloride (0.34 mL, 4.35 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. Methylene chloride (10 mL) was added, and the mixture washed twice with 1N HCl, then twice with 10% aqueous sodium carbonate, and then brine. The organic phase was dried (Na₂SO₄), and evaporated to yield the expected mesylate (0.77 g, 86% yield). Data: ¹HNMR (300 MHz, CDCl₃): δ 7.40 (m, 1H), 7.20 (d, J=3 Hz, 1H), 6.85 (m, 1H), 4.90 (m, 1H), 3.00 (s, 3H).

A solution of the above mesylate (0.77 g, 2.30 mmol) in dimethylformamide (5 mL) was treated with sodium azide (0.66 g, 10.15 mmol) and the mixture heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 499 (0.52, 83% yield) as a yellow oil of suitable purity for use in subsequent reactions.

Synthesis of Triazole 410

A solution of alkyne 173 (100 mg, 0.127 mmol) in tetrahydrofuran (10 mL) was treated with azide 499 (0.05 g, 0.19 mmol), N,N-diisopropylethylamine (0.03 mL, 0.15 mmol) and copper (I) iodide (0.02 g, 0.127 mmol), and the mixture was stirred under argon at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried and evaporated. The residue was purified by preparative thin layer chromatography (using 90% CH₂Cl₂, 0% MeOH, 0.1% NH₄OH as eluant) to provide 410 (71 mg, 77% yield) as a yellow solid. Data for 410: ¹HNMR (300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 7.32 (m, 1H), 7.10 (s, 1H), 6.80 (t, J=3 Hz, 1H), 5.0 (m, 1H), 4.60-4.35 (m, 2H), 4.01 (m, 1H), 3.6 (m, 1H).

Synthesis of Triazole 411

This compound was made from alkyne 173 and the required 3-(4-chlorophenoxy)phenyl isoxazoline azide (synthesized from 3-(4-chlorophenoxy)benzaldehyde using the same procedure described above for the synthesis of azide 499) using the same procedure described above for the synthesis of triazole 410. Data for 411: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 7.10-7.30 (m, 4H), 6.90 (s, 1H), 6.80 (s, 1H), 5.02 (m, 1H), 4.50-4.70 (m, 2H), 4.35 (d, J=3 Hz, 1H), 4.0 (m, 1H), 3.60 (t, J=7 Hz, 2H).

Example 58 Synthesis of Triazoles 412-414

These triazoles were synthesized using the chemistry illustrated for triazole 412 shown in Scheme 78. Hydroxyiminoyl chloride 501 was converted to chiral, non-racemic alcohol 502 which was transformed to azide 503. The cycloaddition of alkyne 173 with azide 503 yielded triazole 412.

Synthesis of Azide 503

A solution of 3,5-difluorobenzaldehyde (2.0 g, 14.0 mmol) and hydroxylamine hydrochloride (1.07 g, 15.4 mmol) in ethanol (40 mL) and water (80 mL) was cooled to 4° C., and 2.3 mL NaOH (50% w/w) was added. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was adjusted to pH 6.0, and partitioned with methylene chloride and water. The aqueous layer was extracted twice with methylene chloride, and the combined organic layer was washed with brine, dried (Na₂SO₄), and evaporated to yield 500 (2.01 g, 91% yield) as a white solid. Data for 500: ¹HNMR (300 MHz, CDCl₃): δ 7.82 (s, 1H), 6.80 (m, 1H), 6.60 (m, 1H).

To a solution of oxime 500 (2.01 g, 12.7 mmol) in dimethylformamide (10 mL) was added N-chlorosuccinimide (1.7 g, 12.7 mmol). The reaction mixture was warmed to 50° C. for 1 h. The reaction was diluted with ethyl acetate (50 mL), and washed with brine. The organic phase was dried (Na₂SO₄), and evaporated to yield 501 (2.45 g, 100% yield). Data for 501: ¹HNMR (300 MHz, CDCl₃): δ 8.0 (s, 1H), 7.40 (d, J=2 Hz, 1H), 6.80 (m, 1H).

To a solution of allyl alcohol (0.7 mL, 10.30 mmol) in 20 mL CHCl₃ was added a 1 M diethylzinc solution in hexane (12.4 mL, 12.40 mmol) at −5 to 0° C. After stirring for 10 min, (+)-diisopropyl tartrate (0.5 mL, 2.10 mmol) was added and the solution was stirred for 1 h at 0° C. The milky solution was cooled to −20° C. and 20 mL CHCl₃ and dioxane (5 mL) was added. Then hydroximinoyl chloride 501 (1.80 g, 9.40 mmol) was added in portions at −20 to −15° C. The solution was stirred for 3 h at −150° C., then poured into 100 mL saturated aqueous NH₄Cl and extracted with CHCl₃ (3×100 mL). The combined organic extract was washed with brine, dried Na₂SO₄, and evaporated. The residue was purified by flash-chromatography (eluting with 30% ethyl acetate/hexane), to afford crude material which was recrystallized from ethyl acetate and hexane to yield 502 (0.75 g, 75% yield). Data for 502: ¹HNMR (300 MHz, CDCl₃): δ 7.20 (m, 2H), 6.80 (m, 1H), 4.96 (m, 1H), 3.90 (m, 1H), 3.70 (m, 1H), 3.30 (m, 2H), 2.10 (m, 1H).

Alcohol 502 (0.74 g, 3.47 mmol) was dissolved in 10 mL methylene chloride, and the mixture cooled to 0° C. Triethylamine (1.0 mL, 6.94 mmol) was added, followed by methanesulfonyl chloride (0.4 mL, 4.85 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. Methylene chloride (10 mL) was added, and the mixture washed twice with 1 N HCl, then twice with 10% aqueous sodium carbonate, and then brine. The organic phase was dried (Na₂SO₄), and evaporated to yield the mesylate (0.93 g, 92% yield). Data: ¹HNMR (300 MHz, CDCl₃): δ 7.15 (m, 2H), 6.85 (m, 1H), 5.01 (m, 1H), 4.33 (m, 2H), 3.00 (s, 3H)

A solution of the above mesylate (0.93 g, 3.19 mmol) in dimethylformamide (10 mL) was treated with sodium azide (0.83 g, 12.7 mmol) and the mixture heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 503 (0.65, 86% yield) as a yellow oil of suitable purity for use in subsequent reactions. Data for 503: ¹HNMR (300 MHz, CDCl₃): δ 7.20 (m, 2H), 6.80 (m, 1H), 4.95 (m, 1H), 3.54 (dd, J=4, 15 Hz, 1H), 3.00 (dd, J=7, 10 Hz, 1H).

Synthesis of Triazole 412

A solution of alkyne 173 (100 mg, 0.127 mmol) in tetrahydrofuran (10 mL) was treated with azide 503 (0.045 g, 0.19 mmol), N,N-diisopropylethylamine (0.03 mL, 0.15 mmol) and copper (I) iodide (0.02 g, 0.127 mmol), and the mixture was stirred under argon at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried and evaporated. The residue was purified by preparative thin layer chromatography (using 80% CH₂Cl₂, 20% MeOH, 0.1% NH₄OH as eluant) to provide 412 (96 mg, 74% yield) as a yellow solid. Data for 412: ¹HNMR (300 MHz, CDCl₃, partial): δ 8.50 (s, 1H), 7.10 (m, 1H), 7.00 (m, 1H), 6.80 (m, 1H), 5.10 (m, 1H), 4.70-4.50 (m, 2H), 4.01 (m, 1H), 3.80 (m, 1H).

Synthesis of Triazole 413

This compound was made from alkyne 173 and the required 3,5-dichlorophenyl isoxazoline azide (produced from 3,5-dichlorobenzaldehyde as described above for the synthesis of azide 503) using the same procedure described above for the synthesis of 412. Data for 413: ¹H-NMR (300 MHz, CDCl₃, partial): δ 9.20 (s, 1H), 7.50 (m, 1H), 7.35 (m, 1H), 5.10 (m, 2H), 4.90 (m, 1H), 4.60 (d, J=5 Hz, 1H), 4.50 (m, 2H), 4.40 (d, J=3 Hz, 1H), 4.00 (m, 1H), 3.60 (m, 2H), 3.20 (s, 3H).

Synthesis of Triazole 414

This compound was made from alkyne 173 and the required piperonyl isoxazoline azide (produced from piperonaldehyde as described above for the synthesis of azide 503) using the same procedure described above for the synthesis of 412. Data for 414: ¹H-NMR (300 MHz, CDCl₃, partial): δ 8.80 (s, 1H), 7.30 (m, 1H), 7.20 (s, 1H), 7.00 (m, 1H), 6.80 (m, 1H), 6.0 (s, 1H), 4.95 (m, 2H), 4.80-4.20 (m, 8H), 4.00 (m, 1H), 3.70 (t, J=3 Hz, 3H).

Example 59 Synthesis of Thiazole 415

Scheme 79 depicts the synthesis of thiazole 415. Mesylate 504 was converted to nitrile 505 which was then hydrolyzed to afford amide 506. Amide 506 was treated with Lawesson's reagent to give the thioamide 507, which was subsequently converted to thiazole 509 by heating in the presence of acyl bromide 508. Alkyation of amine 171 then provided thiazole 415.

Synthesis of Bromide 509

Under an argon atmosphere, a mixture of mesylate 504 (1.67 g, 5 mmol; for a synthesis see Example 39) and NaCN (1.25 g, 25 mmol) in 15 mL of DMF was heated at 120° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with brine, dried (MgSO₄), concentrated and crystallized in EtOAc/hexane to afford nitrile 505 (1.20 g, 90% yield). Data for 505: ¹HNMR (300 MHz, CDCl₃): δ 7.56 (d, J=9 Hz, 2H), 7.53 (d, J=9 Hz, 2H), 5.05 (m, 1H), 3.60 (dd, J=11, 17 Hz, 1H), 3.25 (dd, J=6, 17 Hz, 1H), 2.51 (dd, J=5, 17 Hz, 1H), 2.73 (dd, J=7, 17 Hz, 1H).

A mixture of nitrile 505 (1.0 g, 3.77 mmol) and KOH (0.5 g, 8.93 mmol) in 16 mL of tert-butanol and 2 mL of water was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and diluted with water. The desired amide 506 was collected by filtration (0.85 g, 80% yield). Data for 506: ¹HNMR (300 MHz, DMSO): δ 7.66 (d, J=8 Hz, 2H), 7.61 (d, J=8 Hz, 2H), 7.43 (s, 1H), 6.97 (s, 1H), 4.99 (m, 1H), 3.52 (dd, J=11, 17 Hz, 1H), 3.15 (dd, J=7, 17 Hz, 1H), 2.51 (dd, J=7, 14 Hz, 1H), 2.39 (dd, J=7, 14 Hz, 1H).

A mixture of 506 (220 mg, 0.78 mmol) and Lawesson's reagent (187 mg, 0.46 mmol) in THF (3 mL) was refluxed under argon for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO₄ and concentrated under vacuum. Recrystallization of the crude product from EtOAc afforded 507 (180 mg, 77% yield). Data for 507: MS (ESI) m/z 298.8 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.56 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.46 (br s, 2H), 5.15 (m, 1H), 3.52 (dd, J=10, 17 Hz, 1H), 3.27 (dd, J=8, 17 Hz, 1H), 3.12 (d, J=12 Hz, 2H).

To a solution of 508 (190 mg, 0.83 mmol; prepared as in Eur. J. Org. Chem. 2001, pp. 3789-3795) in THF (8 mL) and MeOH (2 mL) was added 507 (150 mg, 0.50 mmol). After refluxing for 2 h, the reaction was concentrated and crystallized in CH₂Cl₂ to provide 509 (163 mg, 77% yield). Data for 509: MS (ESI) m/z 430.7 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.56 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.41 (s, 1H), 5.26 (m, 1H), 4.02 (dd, J=4, 15 Hz, 1H), 3.85-3.75 (m, 3H), 3.69-3.47 (m, 4H).

Synthesis of Thiazole 415

A mixture of 509 (56 mg, 0.13 mmol), amine 171 (96 mg, 0.13 mmol), Hunig's base (170 mg, 1.3 mmol) and KI (22 mg, 0.13 mmol) in THF (4 mL) was refluxed for 24 h. The THF was removed under vacuum and the residue was dissolved in EtOAc. The solution was washed with brine, dried over MgSO₄, concentrated and purified by chromatography on silica gel (eluant: 25:1:0.1/CH₂Cl₂:MeOH:NH₃.H₂O) to provide thiazole 415 (52 mg, 37% yield). Data for 415: MS (ESI) m/z 1083.7 (M+H)⁺, 542.2 (100%); ¹HNMR (300 MHz, CDCl₃, partial): δ 7.46 (s, 4H), 6.78 (s, 1H), 5.10 (m, 1H), 3.24 (s, 3H), 0.83 (t, J=7 Hz, 3H).

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. 

1. A method of treating a disease in a mammal, wherein the disease is selected from microbial infection, fungal infection, proliferative disease, viral infection, inflammatory disease, and gastrointestinal motility disorder, comprising administering a compound having the formula:

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein A at each occurrence, is carbon; B is selected from the group consisting of O, NR², S(O)_(r), C═O, C═S, and C═NOR³, p is 0; q, at each occurrence, independently is 0 or 1; r is 0, 1, or 2; R², at each occurrence, independently is selected from the group consisting of: a) hydrogen, b) S(O)_(r)R⁴, c) formyl, d) C₁₋₈ alkyl, e) C₂₋₈ alkenyl, f) C₂₋₈ alkynyl, g) C₁₋₈ alkoxy, h) C₁₋₈ alkylthio, i) C₁₋₈ acyl, j) saturated, unsaturated, or aromatic C₃₋₈ carbocycle, and k) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein any of d)-k) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO₂, —NR³R³, —OR³—S(O)_(r)R⁴, S(O)_(r)NR³R³, —C(O)R³, —C(O)OR³, —OC(O)R³, —C(O)NR³R³, and —OC(O)NR³R³; alternatively, two R² groups, taken together with the atom to which they are bonded, form i) 5-8 membered saturated or unsaturated carbocycle, or ii) 5-8 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein i)-ii) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO₂, —NR³R³, —OR³, —S(O)_(r)R⁴—S(O)_(r)NR³R³, —C(O)R³, —C(O)OR³, —OC(O)R³—C(O)NR³R³, —OC(O)NR³R³C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R³, at each occurrence, independently is selected from the group consisting of: a) hydrogen, b) C₁₋₈ alkyl, c) C₂₋₈ alkenyl, d) C₂₋₈ alkynyl, e) C₁₋₈ acyl, f) saturated, unsaturated, or aromatic C₃₋₈ carbocycle, and g) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein any of b)-h) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO₂, —NR⁶R⁶, —OR⁶, —S(O)_(r)R⁶, —S(O)_(r)NR⁶R⁶, —C(O)R⁶—C(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁶, —OC(O)NR⁶R⁶, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; alternatively, two R³ groups, taken together with the atom to which they are bonded, form i) a 5-7 membered saturated or unsaturated carbocycle, or ii) a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein i)-ii) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO₂, —NR⁶R⁶, —OR⁶, S(O)_(r)R⁶, S(O)_(r)NR⁶R⁶, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁶, —OC(O)NR⁶R⁶, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R⁴ is selected from the group consisting of: a) hydrogen, b) —NR³R³, c) —NR³OR³, d) —NR³NR³R³ e) —NHC(O)R³, f) —C(O)NR³R³, g) —N₃, h) C₁₋₈ alkyl, i) C₂₋₈ alkenyl, j) C₂₋₈ alkynyl, k) saturated, unsaturated, or aromatic C₃₋₈ carbocycle, and 1) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein any of h) —1) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO₂, —NR³R³, —OR³, —SR³, S(O)_(r)R⁵, —S(O)_(r)NR³R³, —C(O)R³, —C(O)OR³, —OC(O)R³, —C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R⁵ is selected from the group consisting of: a) hydrogen, b) —NR³R³, c) —NR³OR³, d) —NR³NR³R³ e) —NHC(O)R³, f) —C(O)NR³R³, g) —N₃, h) C₁₋₈ alkyl, i) C₂₋₈ alkenyl, j) C₂₋₈ alkynyl, k) saturated, unsaturated, or aromatic C₃₋₈ carbocycle, and l) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein any of h)-l) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, CN, NO₂, —NR³R³, —OR³—SR³—C(O)R³, —C(O)OR³, —OC(O)R³, —C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R⁶, at each occurrence, independently is selected from the group consisting of: hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; alternatively, two R⁶groups taken together are —(CH₂)_(s)—, wherein s is 1, 2, 3, 4, or 5; D-E is:

E is selected from the group consisting of:

d) 5-10 membered aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R¹³ groups; and e) C₅₋₁₀ aromatic carbocycle, optionally substituted with one or more R¹³ groups; R⁷ is selected from the group consisting of: a) hydrogen, b) carbonyl, c) formyl, d) F, e) Cl, f) Br, g) I, h) CN, i) NO₂, j) OR³, k) —S(O)_(r)R⁵, l) —S(O)_(i)N═R², m) —C(O)R², n) —C(O)OR³, o) —OC(O)R², p) —C(O)NR²R², q) —OC(O)NR²R², r) —C(═NR²)R², s) —C(R²)(R²)OR³, t) —C(R²)(R²)OC(O)R², u) —C(R²)(OR³)(CH₂)_(r)NR²R², v) —NR²R², w) —NR²OR³, x) —N(R²)C(O)R², y) —N(R²)C(O)OR³, z) —N(R²)C(O)NR²R², aa) —N(R²)S(O)_(r)R⁵, bb) —C(OR⁶)(OR)R², cc) —C(R²)(R³)NR²R², dd) —C(R²)(R³)NR²R², ee) ═NR², ff) —C(S)NR²R², gg) —N(R²)C(S)R², hh) —OC(S)NR²R², ii) —N(R²)C(S)OR³, jj) —N(R²)C(S)NR²R², kk) —SC(O)R², ll) C₁₋₈ alkyl, mm) C₂₋₈ alkenyl, nn) C₂₋₈ alkynyl, oo) C₁₋₈ alkoxy, pp) C₁₋₈ alkylthio, qq) C₁₋₈ acyl, m) saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle, and ss) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein any of ll)-ss) optionally is substituted with one or more moieties selected from the group consisting of: carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³; —S(O)_(r)R⁵; —S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²; —C(O)NR²R²; —OC(O)NR²R²; —C(═NR¹⁰)R²; —C(R²)(R²)OR³; —C(R²)(R²)OC(O)R^(2 —C(R) ²)(OR³)(CH₂)_(r)NR²R²; —NR²R²; —NR²OR′; —NR²C(O)R²; —NR²C(O)OR³; —NR²C(O)NR²R²; —NR²S(O)_(r)R⁵; —C(OR⁶)(OR⁶)R²; —C(R²)(R³)NR²R²; —C(R²)(R³)NR²R¹²; ═NR¹²; —C(S)NR²R²; —NR²C(S)R²; —OC(S)NR²R²; —NR²C(S)OR³; —NR²C(S)NR²R²; —SC(O)R²; C₂₋₅ alkenyl; C₂₋₅ alkynyl; C₁₋₈ alkoxy; C₁₋₈ alkylthio; C₁₋₈ acyl; saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle, optionally substituted with one or more R⁸ groups; and saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R⁸ groups; R⁸ is selected from the group consisting of: hydrogen; F; Cl; Br; I; CN; NO₂; OR⁶; aryl; substituted aryl; heteroaryl; substituted heteroaryl; and C₁₋₆ alkyl, optionally substituted with one or more moieties selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO₂, and OR⁶; alternatively, R⁷ and R⁸ taken together are —O(CH₂)_(r)C—; R⁹, at each occurrence, independently is selected from the group consisting of: hydrogen, F, Cl, Br, I, CN, OR³, NO₂, —NR²R², C₁₋₆ alkyl, C₁₋₆ acyl, and C₁₋₆ alkoxy; R¹⁰ is selected from the group consisting of: a) saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle, b) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, c) —X—C₁₋₆ alkyl-saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, d) saturated, unsaturated, or aromatic 10-membered bicyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, e) saturated, unsaturated, or aromatic 13-membered tricyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and f) R⁹, wherein any of a)-e) optionally is substituted with one or more R¹³groups, and X is O or NR³; alternatively, R¹⁰ and one R⁹ group, taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R¹³ groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R¹³ groups; R¹¹ at each occurrence, independently is selected from the group consisting of: hydrogen; an electron-withdrawing group; aryl; substituted aryl; heteroaryl; substituted heteroaryl; and C₁₋₆ alkyl, optionally substituted with F, Cl, or Br; alternatively, any R¹¹ and R⁸, taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R¹³ groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R¹³ groups; R¹² is selected from the group consisting of: —NR²R², —OR³, —OC(O)R², —OC(O)OR³, —NR²C(O)R², —NR²C(O)NR²R², —NR²C(S)NR²R², and —NR²C(═NR²)NR²R²; R¹³, at each occurrence, independently is selected from the group consisting of: a) hydrogen, b) carbonyl, c) formyl d) F, e) Cl, f) Br, g) I, h) CN, i) NO₂, j) OR³, k) —S(O)_(r)R⁵, l) —S(O)_(r)N═R³, m) —C(O)R², n) —C(O)OR³, o) —OC(O)R², p) —C(O)NR²R², q) —OC(O)NR²R², r) —C(═NR¹²)R², s) —C(R²)(R²)OR³, t) —C(R²)(R²)OC(O)R², u) —C(R²)(OR³)(CH₂)_(r)NR²R², v) —NR²R², w) —NR¹OR³, x) —N(R²)C(O)R², y) —N(R²)C(O)OR³, z) —N(R²)C(O)NR²R², aa) —N(R²)S(O)_(r)R⁵, bb) —C(OR⁶)(OR⁶)R², cc) —C(R²)(R³)NR²R², dd) —C(R²)(R³)NR²R¹², ee) ═NR¹², ff) —C(S)NR²R², gg) —N(R²)C(S)R², hh) —OC(S)NR²R², ii) —N(R²)C(S)OR³, jj) —N(R²)C(S)NR²R², kk) —SC(O)R², ll) C₁₋₈ alkyl, mm) C₂₋₈ alkenyl, nn) C₂₋₈ alkynyl, oo) C₁₋₈ alkoxy, pp) C₁₋₈ alkylthio, qq) C₁₋₈ acyl, m) saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle, ss) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, tt) saturated, unsaturated, or aromatic 10-membered bicyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and uu) saturated, unsaturated, or aromatic 13-membered tricyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein any of ll)-uu) optionally is substituted with one or more moieties selected from the group consisting of: carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³; —S(O)_(r)R⁵; —S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²; —C(O)NR²R²; —OC(O)NR²R²; —C(═NR¹²)R²; —C(R²)(R²)OR³; —C(R²)(R²)OC(O)R²; —C(R²)(OR³)(CH₂)_(r)NR²R²; —NR²R²; —NR²OR³; —NR²C(O)R²; —NR²C(O)OR; —NR²C(O)NR²R²; —NR²S(O)_(r)R⁵; —C(OR⁶)(OR⁶)R²; —C(R²)(R³)NR²R²; —C(R²)(R³)NR²R²; ═NR²; —C(S)NR²R²; —NR²C(S)R²; —OC(S)NR²R²; —NR²C(S)OR³; —NR²C(S)NR²R²; —SC(O)R²; C₁₋₈ alkyl, C₂₋₈ alkenyl; C₂₋₈ alkynyl; C₁₋₈ alkoxy; C₁₋₈ alkylthio; C₁₋₈ acyl; saturated, unsaturated, or aromatic C₃₋₁₀ carbocycle optionally substituted with one or more R⁷ groups; and saturated, unsaturated, or aromatic 3-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and substituted with one or more R⁷ groups; G is selected from the group consisting of:

t, at each occurrence, independently is 0, 1, 2, or 3; R¹⁴ is selected from the group consisting of: a) hydrogen, b) C₁₋₆-alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆ alkynyl, e) —C(O)—R³, f) —C(O)—C₁₋₆ alkyl-R³, g) —C(O)—C₂₋₆ alkenyl-R³, h) —C(O)—C₂₋₆ alkynyl-R³, i) —C₁₋₆ alkyl-J-R³, j) —C₂₋₆ alkenyl-J-R³; and k) —C₂₋₆ alkynyl-J-R³; wherein (i) any of b)-d) optionally is substituted with one or more substituents selected from the group consisting of: F, Cl, Br, I, aryl, substituted aryl, heteroaryl, substituted heteroaryl, —OR³, —O—C₁₋₆ alkyl-R²², —O—C₂₋₆ alkenyl-R²², —O—C₂₋₆ alkynyl-R³, and —NR²R²; and (ii) J is selected from the group consisting of: —OC(O), —OC(O)O—, —OC(O)NR²—, —C(O)NR²—, —NR²C(O—, —NR²C(O)O—, —NR²C(O)NR²—, —NR²C(NH)NR²—, and S(O)_(r); and R¹⁵ is selected from the group consisting of: hydrogen; C₁₋₁₀ alkyl, optionally substituted with one or more R¹³ groups; C₁₋₆ acyl, optionally substituted with one or more R¹³ groups; aryl; substituted aryl; heteroaryl; substituted heteroaryl; arylalkyl; substituted arylalkyl; and a macrolide.
 2. The method of claim 1, wherein the compound is administered orally, paternally, or topically.
 3. The method of claim 1, wherein the disease is a microbial infection.
 4. The method of claim 1, wherein the disease is a fungal infection.
 5. The method of claim 1, wherein the disease is a proliferative disease.
 6. The method of claim 1, wherein the disease is a viral infection.
 7. The method of claim 1, wherein the disease is an inflammatory disease.
 8. The method of claim 1, wherein the disease is a gastrointestinal motility disorder.
 9. The method of claim 1, wherein the compound has the formula:

wherein A, E, and G are as defined in claim
 1. 10. The method of claim 1, wherein E has the formula:

wherein R⁹ and R¹⁰, at each occurrence, are as defined in claim
 1. 11. The method of claim 1, wherein E has the formula:

wherein R¹⁰ is as defined in claim
 1. 12. The method of claim 10, wherein R¹⁰ has the formula:

wherein K is selected from the group consisting of O, NR², and S(O)_(r), and x is 0, 1, 2, or
 3. 13. The method of claim 12, wherein K is oxygen.
 14. The method of claim 12, wherein x is
 1. 15. The method of claim 1, wherein G has the formula selected from the group consisting of:

and R¹⁵ is a macrolide.
 16. The method of claim 1, wherein R¹⁵ is selected from the group consisting of:

and pharmaceutically acceptable salts, esters and prodrugs thereof, wherein R¹⁷ is selected from the group consisting of: hydrogen, hydroxy protecting group, R³, and —V—W—R¹³, wherein V is —C(O), —C(O)O—, —C(O)NR²—, or absent, and W is C₁₋₆ alkyl, or absent; alternatively R¹⁷ and R¹⁴, taken together with the atoms to which they are bonded, form:

Q is selected from the group consisting of: —NR²CH₂—, —CH₂—NR²—, —C(O)—, —C(═NR²)—, —C(═NOR³)—, —C(═N—NR²R²)—, —CH(OR³)—, and —CH(NR²R²; R¹⁸ is selected from the group consisting of: i) C₁₋₆ alkyl, ii) C₂₋₆ alkenyl, and iii) C₂₋₆ alkynyl; wherein any of i) —11i) optionally is substituted with one or more moieties selected from the group consisting of —OR³, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R¹⁹ is selected from the group consisting of: a) —OR¹⁷, b) C₁₋₆alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆ alkynyl, e) —NR²R², f) —C(O)R³, g) —C(O)—C₁₋₆ alkyl-R¹³, h) —C(O)—C₂₋₆ alkenyl-R³, and i) —C(O)—C₂₋₆ alkynyl-R¹³, wherein any of b)-d) optionally is substituted with one or more R¹³ groups; alternatively, R¹⁴ and R¹⁹, taken together with the atoms to which they are bonded, form:

wherein L is CH or N, and R²³ is —OR³, or R³; R²⁰ is —OR¹⁷; alternatively, R¹⁹ and R²⁰, taken together with the atoms to which they are bonded, form a 5-membered ring by attachment to each other through a linker selected from the group consisting of: —OC(R²)(R²)O—, —OC(O)O—, —OC(O)NR²—, —NR²C(O)O—, —OC(O)NOR³—, —N(OR³)C(O)O—, —OC(O)N—NR²R²—, —N(NR²R²)C(O)O—, —OC(O)CHR²—, —CHR²C(O)O—, —OC(S)O—, —OC(S)NR²—, —NR²C(S)O—, —OC(S)NOR³—, —N(OR³)C(S)O—, —OC(S)N—NR²R²—, —N(NR²R²)C(S)G, —OC(S)CHR²—, and —CHR²C(S)O—; alternatively, Q, R¹⁹, and R²⁰, taken together with the atoms to which they are bonded, form:

wherein M is O or NR²; R²¹ is selected from the group consisting of: hydrogen, F, Cl, Br, and C₁₋₆ alkyl; R²², at each occurrence, independently is selected from the group consisting of: hydrogen, —OR³, —O-hydroxy protecting group, —O—C-6 alkyl-J-R¹³, —O—C₂₋₆ alkenyl-J-R¹, —O—C₁₋₆ alkynyl-J-R³, and —NR²R²; alternatively, two R²² groups taken together are ═O, ═N—OR³, or ═N—NR²R²; and R², R³, R¹³, R¹⁴, and J are as described in claim
 1. 17. The method of claim 1, wherein G has the formula selected from the group consisting of:

and R¹⁵ has the formula selected from the group consisting of:


18. The method of claim 1, wherein G has the formula:

wherein n=1, 2, 3, or
 4. 19. The method of claim 1, wherein G has the formula selected from the group consisting of:


20. The method of claim 1, comprising a compound having the structure corresponding to any of the structures listed below:

or a pharmaceutically acceptable salt, ester, or prodrug thereof. 